JP4467889B2 - Broad range 2-amino-benzoxazolesulfonamide HIV protease inhibitors - Google Patents

Description

  The present invention relates to 2-amino-benzoxazolesulfonamides, aspartic protease inhibitors, in particular their use as broadspectrum HIV protease inhibitors, processes for their preparation and pharmaceutical compositions and diagnostic kits containing them. . The invention also relates to the combination of the 2-aminobenzoxazolesulfonamide with other anti-retroviral drugs. The invention further relates to their use as reference compounds or as reagents in assays.

  Viruses that cause acquired immunodeficiency syndrome (AIDS) are T-lymphocyte virus III (HTLV-III) or lymphadenopathy-related virus (LAV) or AIDS-related virus (ARV) or human immunodeficiency virus (HIV). It is known by various names including. To date, two distinct groups have been identified: HIV-1 and HIV-2. In the following, HIV is used to generically denote these viruses.

  One important pathway in the retroviral life cycle is the processing of polyprotein precursors by aspartic proteases. For example, in the case of HIV virus, the gag-pol protein is processed by HIV protease. The assembly of infectious virions requires the correct processing of the precursor polyprotein by aspartic proteases, thus making aspartic proteases an attractive target for antiviral therapy. Particularly for HIV treatment, HIV protease is an attractive target.

  HIV protease inhibitors (PIs) are usually other anti-HIV compounds such as nucleoside reverse transcriptase inhibitors (NRTIs), non-nucleoside reverse transcriptase inhibitors (NNRTIs), nucleotide reverse transcriptase inhibitors (NtRTIs) or others In combination with other protease inhibitors. Despite the great usefulness of these antiretroviral drugs, they have a common limitation, i.e., the target enzyme in the HIV virus can be mutated, which causes these mutant HIV viruses to In contrast, the effectiveness of known drugs is reduced or ineffective. Or, in other words, the HIV virus produces a constantly increasing resistance to available drugs.

  Resistance to inhibitors of retroviruses, and particularly HIV viruses, is a major cause of treatment failure. For example, half of patients receiving anti-HIV combination therapy do not respond well to treatment due to the resistance of the virus to one or more drugs used primarily. In addition, resistant viruses have been carried over to newly infected patients and have been shown to severely limit treatment options for these drug-naive patients. Accordingly, there is a need in the art for new compounds for retrovirus therapy, and more specifically for AIDS therapy. The need in the art is particularly urgent for compounds that are active not only on wild-type HIV viruses but also on increasingly resistant resistant HIV viruses.

  Known antiretroviral drugs, often administered in combination therapy management, eventually develop resistance as described above. This may often force the physician to increase the plasma level of the active agent in order to regain its effectiveness against the mutated HIV virus. The result is a highly undesirable increase in drug burden. Increasing plasma levels can also increase the risk of non-compliance with the prescribed treatment. Thus it is not only important to have compounds that exhibit activity on a wide range of HIV mutants, but also the ratio between activity against mutant HIV virus and activity against wild type HIV virus (also defined as fold resistance or FR) It is also important that there is little or no variation in a wide range of mutant HIV strains. At such times, the patient can remain on the same combination therapy regimen for a longer time, as the chance of the mutant HIV virus being sensitive to the active ingredient increases.

  Finding compounds with high titers in wild-type and diverse mutant strains is important because drug loading can be reduced if therapeutic levels are kept to a minimum. One method of reducing this drug load has excellent bioavailability, ie favorable pharmacokinetic and metabolic aspects, minimizing daily doses and minimizing the number of drugs that must eventually be taken. To find anti-HIV compounds that can be made.

  Another important property of a good anti-HIV compound is that the plasma protein binding of the inhibitor has minimal or no effect on its potency.

  Thus, it can protect against a wide range of mutants of HIV virus with little variation in fold resistance, has excellent bioavailability and has little or no effect on their titer due to plasma protein binding. There is a high medical need for protease inhibitors that do not.

  To date, several protease inhibitors have been marketed or developed. One specific core structure (shown below) is disclosed in multiple references, for example, Patent Document 1, Patent Document 2, Patent Document 3, Patent Document 4, Patent Document 5, Patent Document 6, and Patent Document 7. . The compounds disclosed therein are described as retroviral protease inhibitors.

  U.S. Patent No. 6,057,031 discloses 4-substituted-phenylsulfonamides that can inhibit multidrug resistant retroviral protease.

International Publication No. 95/06030 Pamphlet International Publication No. 96/22287 Pamphlet International Publication No. 96/28418 Pamphlet International Publication No. 96/28463 Pamphlet International Publication No. 96/28464 Pamphlet International Publication No. 96/28465 Pamphlet International Publication No. 97/18205 Pamphlet International Publication No. 99/67254 Pamphlet

  Surprisingly, it has been found that the 2-amino-benzoxazole sulfonamides of the present invention have favorable pharmacological and pharmacokinetic aspects. Not only are they active against wild-type HIV viruses, they also exhibit a wide range of activities against various mutant HIV viruses that are resistant to known protease inhibitors.

  The present invention is a formula

[Where:
R ₁ and R ₈ are each independently hydrogen, C _1-6 alkyl, C _2-6 alkenyl, aryl C _1-6 alkyl, C _3-7 cycloalkyl, C _3-7 cycloalkyl C _1-6 alkyl, Aryl, Het ¹ , Het ¹ C _1-6 alkyl, Het ² , Het ² C _1-6 alkyl;
R ₁ is also the formula

Can also be a group of
Here, R ₉ , R _10a and R _10b are each independently hydrogen, C _1-4 alkyloxycarbonyl, carboxyl, aminocarbonyl, mono- or di (C _1-4 alkyl) aminocarbonyl, C _3-7 cycloalkyl. , _{C 2-6 alkenyl, C 2-6} alkynyl or optionally _{^{aryl, Het 1, Het 2, C}} 3-7 _{cycloalkyl, C 1-4} alkyloxycarbonyl, carboxyl, aminocarbonyl, mono- - or di _{(C 1 -4} alkyl) aminocarbonyl, aminosulfonyl, C _1-4 alkyl S (O) _t, hydroxy, cyano, mono- halogen or - could have been or disubstituted, where the substituents are each independently C _1-4 alkyl, aryl, aryl _{C 1-4 alkyl, C 3- C 1} which can be substituted with _{cycloalkyl, C 3-7} cycloalkyl _{C 1-4} ^{alkyl, Het 1, Het 2, Het} 1 C 1-4 amino selected from alkyl and ^Het 2 _{C 1-4} alkyl There _-4 alkyl; wherein _{R 9, R 10a} and their carbon atom bonded also can form a _{C 3-7} cycloalkyl group; L is _{-O-C 1-6} alkanediyl - In the case of C (═O) — or —NR ₈ —C _1-6 alkanediyl-C (═O) —, R ₉ can also be oxo;
R _11a is hydrogen, C _2-6 alkenyl, C _2-6 alkynyl, C _3-7 cycloalkyl, aryl, optionally mono- or disubstituted aminocarbonyl, optionally mono- or disubstituted Amino C _1-4 alkylcarbonyloxy, C _1-4 alkyloxycarbonyl, aryloxycarbonyl, Het ¹ oxycarbonyl, Het ² oxycarbonyl, aryloxycarbonyl C _1-4 alkyl, aryl C _1-4 Alkyloxycarbonyl, C _1-4 alkylcarbonyl, C _3-7 cycloalkylcarbonyl, C _3-7 cycloalkyl C _1-4 alkyloxycarbonyl, C _3-7 cycloalkylcarbonyloxy, carboxyl C _1-4 alkylcarbonyloxy , C _-4 alkylcarbonyloxy, aryl _{C 1-4} alkylcarbonyloxy, arylcarbonyloxy, aryloxycarbonyloxy, Het ¹ carbonyl, Het ^{1 carbonyloxy,} Het _{1 C 1-4} alkyloxycarbonyl, Het ² carbonyloxy, Het ² C _1-4 ^{alkylcarbonyloxy,} Het _{2 C 1-4} alkyloxycarbonyloxy or optionally aryl, aryloxy, be a _{C 1-4} alkyl which may be substituted with Het ² or hydroxy; amino group wherein The above substituents are each independently C _1-4 alkyl, aryl, aryl C _1-4 alkyl, C _3-7 cycloalkyl, C _3-7 cycloalkyl C _1-4 alkyl, Het ¹ , Het ² , Het ¹ C _1-4 a Selected from rualkyl and Het ² C _1-4 alkyl;
R _11b is hydrogen, C _3-7 cycloalkyl, C _2-6 alkenyl, C _2-6 alkynyl, aryl, Het ¹ , Het ² or optionally halogen, hydroxy, C _1-4 alkyl S (═O) _t , Aryl, C _3-7 cycloalkyl, Het ¹ , Het ² , optionally mono- or disubstituted, wherein each substituent is independently C _1-4 alkyl, aryl, aryl C _1- Substituted with amino selected from ₄ alkyl, C _3-7 cycloalkyl, C _3-7 cycloalkyl C _1-4 alkyl, Het ¹ , Het ² , Het ¹ C _1-4 alkyl and Het ² C _1-4 alkyl C _1-4 alkyl, which can be
Wherein R _11b can be attached to the rest of the molecule via a sulfonyl group;
each t is independently zero, 1 or 2;
R ₂ is hydrogen or C _1-6 alkyl;
L is -C (= O) -, - O-C (= O) -, - NR 8 -C (= O) -, - O-C 1-6 alkanediyl -C (= O) -, - NR _8- C _1-6 alkanediyl-C (═O) —, —S (═O) ₂ —, —O—S (═O) ₂ —, —NR ₈ —S (═O) ₂ , where In which either the C (═O) group or the S (═O) ₂ group is attached to the NR ₂ moiety; wherein the C _1-6 alkanediyl moiety is optionally from hydroxy, aryl, Het ¹ and Het ² Can be substituted with selected substituents;
R ₃ is C _1-6 alkyl, aryl, C _3-7 cycloalkyl, C _3-7 cycloalkyl C _1-4 alkyl or aryl C _1-4 alkyl;
R ₄ is hydrogen, C _1-4 alkyloxycarbonyl, carboxyl, aminocarbonyl, mono- or di (C _1-4 alkyl) aminocarbonyl, C _3-7 cycloalkyl, C _2-6 alkenyl, C _2-6 alkynyl Or optionally aryl, Het ¹ , Het ² , C _3-7 cycloalkyl, C _1-4 alkyloxycarbonyl, carboxyl, aminocarbonyl, mono- or di (C _1-4 alkyl) aminocarbonyl, aminosulfonyl, C _{1 -4} alkyl S (= O) _t , hydroxy, cyano, halogen and optionally mono- or disubstituted, wherein the substituents are each independently C _1-4 alkyl, aryl, aryl C _{1 -4 alkyl, C 3-7 cycloalkyl, C 3-7} cycloalkyl -C _-4 ^{alkyl, Het 1, Het 2, Het} 1 C 1-4 be substituted with independently one or more substituents selected from amino selected from alkyl and ^Het 2 _{C 1-4} alkyl C _1-6 alkyl which can be
R ₅ is hydrogen or C _1-6 alkyl;
R ₆ is hydrogen or C _1-6 alkyl]
It relates to 2-amino-benzoxazole protease inhibitors having the following and their N-oxides, salts, stereoisomers, racemic mixtures, prodrugs, esters and metabolites.

  The basic nitrogen present in the compound may be quaternized using any agent known to those of ordinary skill in the art including, for example, lower alkyl halides, dialkyl sulfates, long chain halides and aralkyl halides. it can.

  Whenever the term “substituted” is used in the definition of a compound of formula (I), one or more hydrogens on the atom indicated in the expression using “substituted” are indicated. Substituted with one selected from the group (s) being selected, provided that the normal valence of the indicated atom is not exceeded and the substitution is useful from a chemically stable compound, i.e. a reaction mixture. It should yield a compound that is sufficiently robust to be safely isolated to a degree of purity and ready for therapeutic preparation.

  As used herein, the term “halo” or “halogen” as a group or part of a group is a generic term for fluoro, chloro, bromo or iodo.

The term “C _1-4 alkyl” as a group or part of a group refers to straight-chain and branched saturated hydrocarbon groups having 1 to 4 carbon atoms, such as methyl, ethyl, propyl , Butyl and 2-methyl-propyl.

The term “C _1-6 alkyl” as a group or part of a group refers to straight-chain and branched saturated hydrocarbon groups having 1 to 6 carbon atoms, for example C _1-4 alkyl. And the groups defined above with respect to pentyl, hexyl, 2-methylbutyl, 3-methylpentyl and the like.

The term “C _1-6 alkanediyl” as a group or part of a group refers to divalent linear and branched saturated hydrocarbon groups having 1 to 6 carbon atoms, such as methylene. Ethane-1,2-diyl, propane-1,3-diyl, propane-1,2-diyl, butane-1,4-diyl, pentane-1,5-diyl, hexane-1,6-diyl, 2 -Methylbutane-1,4-diyl, 3-methylpentane-1,5-diyl and the like are defined.

As part of a single or a group as a base term "C _2-6 alkenyl" includes straight and branched chain hydrocarbons having from 2 to 6 carbon atoms containing at least one double bond Define a hydrogen group such as ethenyl, propenyl, butenyl, pentenyl, hexenyl, and the like.

The term “C _2-6 alkynyl” as a group or part of a group is a straight-chain and branched hydrocarbon having 2 to 6 carbon atoms containing at least one triple bond Groups such as ethynyl, propynyl, butynyl, pentynyl, hexynyl and the like are defined.

The term “C _3-7 cycloalkyl” as a group or part of a group is a generic term for cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or cycloheptyl.

The term “aryl” as a group or part of a group is intended to include phenyl and naphthyl, both of which are optionally C _1-6 alkyl, optionally mono- or disubstituted amino. C _1-6 alkyl, C _1-6 alkyloxy, halogen, hydroxy, hydroxy C _1-6 alkyl, optionally mono- or disubstituted amino, nitro, cyano, haloC _1-6 alkyl, Carboxyl, C _1-6 alkoxycarbonyl, C _3-7 cycloalkyl, Het ¹ , optionally mono- or disubstituted aminocarbonyl, methylthio, methylsulfonyl and optionally C _1-6 alkyl, optionally mono - or amino C which can be disubstituted _{-6 alkyl, C 1-6} alkyloxy, halogen, hydroxy, optionally mono- - or amino which may optionally disubstituted, nitro, cyano, halo _{C 1-6} alkyl, _{carboxyl, C 1-6} alkoxycarbonyl, C _3-7 cycloalkyl, Het ¹ , optionally substituted with one or more substituents independently selected from aminocarbonyl, methylthio and methylsulfonyl, which may be mono- or disubstituted Can be substituted with one or more substituents independently selected from phenyl; where the optional substituents on the amino function are C _1-6 alkyl, C _1-6 alkyl oxy _{^{-A-, Het 1 -A-, Het 1}} C 1-6 ^alkyl, Het _{1 C 1-6} Alkyl -A-, Het ¹ oxy -A-, Het ¹ oxy _{C 1-4} alkyl -A-, phenyl -A-, phenyl - oxy -A-, phenyloxy _{C 1-4} alkyl -A-, a phenyl _{C 1} Independently selected from _-6 alkyl-A-, C _1-6 alkyloxycarbonylamino-A-, amino-A-, amino C _1-6 alkyl and amino C _1-6 alkyl-A- Each of the groups can optionally be mono- or possibly di-substituted with C _1-4 alkyl, and where A is C _1-6 alkanediyl, —C (═O) —, — C (= S) -, - S (= O) 2 -, C 1-6 alkanediyl _{-C (= O) -, C} 1-6 alkanediyl -C (= S) - or _{C 1-6} alkanediyl -S (= _{O) 2} - are defined as, where The point of attachment of A to the remainder of the child, the moiety containing C _1-6 alkanediyl group is the group.

Interesting subgroups in the definition of “aryl” as a group or as part of a group include phenyl and naphthyl, both optionally C _1-6 alkyl, C _1-6 alkyloxy, halogen, hydroxy, Amino, nitro, cyano, halo C _1-6 alkyl, carboxyl, C _1-6 alkoxycarbonyl, C _3-7 cycloalkyl, Het ¹ , optionally mono- or disubstituted, optionally mono- or Aminocarbonyl, methylthio, methylsulfonyl which can be disubstituted and optionally C _1-6 alkyl, C _1-6 alkyloxy, halogen, hydroxy, optionally mono- or disubstituted amino, Nitro, cyano, halo C _1-6 alkyl, carbo One or more substituents selected from xyl, C _1-6 alkoxycarbonyl, C _3-7 cycloalkyl, Het ¹ , aminocarbonyl, methylthio and methylsulfonyl which may optionally be mono- or disubstituted Can be substituted with one or more substituents independently selected from phenyl, which can be substituted with; optionally substituted on the amino function is C _1-6 alkyl, C _1-6 alkyloxy-A-, Het ¹ -A-, Het ¹ C _1-6 alkyl, Het ¹ C _1-6 alkyl-A-, Het ¹ oxy-A-, Het ¹ oxyC _1-4 alkyl -A-, phenyl -A-, phenyl - oxy -A-, phenyloxy _{C 1-4} alkyl -A-, a phenyl _{C 1-6} alkyl - A-, C _1-6 alkyloxycarbonylamino-A-, amino-A-, amino C _1-6 alkyl and amino C _1-6 alkyl-A-, wherein each amino group is Optionally it can be mono- or optionally di-substituted with C _1-4 alkyl, and A is as defined above.

The term “haloC _1-6 alkyl” as a group or part of a group refers to C ₁ substituted with one or more halogen atoms, preferably chloro or fluoro atoms, more preferably fluoro atoms. Defined as _-6 alkyl. Preferred haloC _1-6 alkyl groups include, for example, trifluoromethyl and difluoromethyl.

The term “ _{hydroxyC 1-6} alkyl” as a group or part of a group is defined as C _1-6 alkyl substituted with one or more hydroxy groups.

The term “Het ¹ ” as a group or part of a group is saturated with 3 to 14 ring members, preferably 5 to 10 ring members and more preferably 5 to 8 ring members. Or a partially unsaturated monocyclic, bicyclic or tricyclic heterocycle, which contains one or more heteroatom ring members each independently selected from nitrogen, oxygen or sulfur and C _1-6 alkyl optionally on one or more carbon atoms, optionally mono- or disubstituted amino C _1-6 alkyl, hydroxy C _1-6 alkyl, C _1-6 alkyl Oxy, halogen, hydroxy, oxo, optionally mono- or disubstituted amino, nitro, cyano, halo C _1-6 al Having a kill, carboxyl, C _1-6 alkoxycarbonyl, C _3-7 cycloalkyl, optionally mono- or disubstituted aminocarbonyl, methylthio, methylsulfonyl, aryl and 3-14 ring members. Substituted by a saturated or partially unsaturated monocyclic, bicyclic or tricyclic heterocycle containing one or more heteroatom ring members each independently selected from nitrogen, oxygen or sulfur Where the optional substituents on the amino function are C _1-6 alkyl, C _1-6 alkyloxy-A-, Het ² -A-, Het ² C _1-6 alkyl, Het ² C _6alkyl -A-, Het ² oxy -A-, Het ² oxy _{C 1-4} alkyl -A-, aryl -A-, Ariruoki -A-, aryloxy _{C 1-4} alkyl -A-, aryl _{C 1-6} alkyl _-A-, -A- _{C 1-6} alkyloxycarbonyl, amino -A-, amino _{C 1-6} alkyl and amino Independently selected from C _1-6 alkyl-A-, wherein each of the amino groups may optionally be mono- or possibly di-substituted with C _1-4 alkyl, and wherein A is as defined above.

An interesting subgroup in the definition of “Het ¹ ” as one group or as part of a group is preferably 3 to 12 ring members, more preferably 5 to 10 ring members and more preferably 5 to 8 Defined as a saturated or partially unsaturated monocyclic, bicyclic or tricyclic heterocycle having one ring member, which contains one or more heteroatom ring members selected from nitrogen, oxygen or sulfur And it may optionally be C _1-6 alkyl, C _1-6 alkyloxy, halogen, hydroxy, oxo, optionally mono- or disubstituted amino, nitro on one or more carbon atoms. , Cyano, halo C _1-6 alkyl, carboxyl, C _1-6 alkoxycarbonyl, C _3-7 cycloalkyl, optionally One or more heteroatom rings selected from nitrogen, oxygen or sulfur having aminocarbonyl, methylthio, methylsulfonyl, aryl and 3-12 ring members, which may be mono- or disubstituted It can be substituted by a saturated or partially unsaturated monocyclic, bicyclic or tricyclic heterocycle containing members, where the optional substituent on the amino function is C _1-6 alkyl, C _1-6 alkyloxy-A-, Het ² -A-, Het ² C _1-6 alkyl, Het ² C _1-6 alkyl-A-, Het ² oxy-A-, Het ² oxyC _1-4 alkyl -A-, aryl -A-, aryloxy -A-, -A- aryloxy _{C 1-4} alkyl, aryl _{C 1-6} alkyl _{-A-, C 1-6} Arukiruo Independently selected from xylcarbonylamino-A-, amino-A-, amino C _1-6 alkyl and amino C _1-6 alkyl-A-, wherein each of the amino groups is optionally C _1-4 alkyl It can be mono- or, where possible, di-substituted, and A is as defined above.

The term “Het ² ” as a group or as part of a group is an aromatic having 3 to 14 ring members, preferably 5 to 10 ring members and more preferably 5 to 6 ring members. Defined as a monocyclic, bicyclic or tricyclic heterocycle, which contains one or more heteroatom ring members each independently selected from nitrogen, oxygen or sulfur and optionally one Or C _1-6 alkyl on more carbon atoms, optionally amino- or di-substituted amino C _1-6 alkyl, hydroxy C _1-6 alkyl, C _1-6 alkyloxy, halogen, hydroxy, optionally mono- - or amino which may optionally disubstituted, nitro, cyano, halo C _1-6 alkyl, carboxyl, C _{1 6} alkoxycarbonyl, C _3-7 cycloalkyl, optionally mono- - or di-substituted aminocarbonyl can have, methylthio, aromatic monocyclic ring having methylsulfonyl, aryl, Het ¹ and 3 to 12 ring members Can be substituted by formula, bicyclic or tricyclic heterocycle; where the optional substituents on the amino function are C _1-6 alkyl, C _1-6 alkyloxy-A-, Het ¹ -A-, Het ¹ C _1-6 alkyl, Het ¹ C _1-6 alkyl-A-, Het ¹ oxy-A-, Het ¹ oxy C _1-4 alkyl-A-, aryl-A-, aryloxy- A-, aryloxy _{C 1-4} alkyl -A-, aryl _{C 1-6} alkyl _{-A-, C 1-6} alkyloxycarbonylamino -A-, amino Independently selected from -A-, amino C _1-6 alkyl and amino C _1-6 alkyl-A-, wherein each amino group is optionally C _1-4 alkyl mono- or, where possible, di- -Can be substituted, wherein A is as defined above.

An interesting subgroup in the definition of “Het ² ” as one group or as part of a group is preferably 3 to 12 ring members, more preferably 5 to 10 ring members and more preferably 5 to 6 Defined as an aromatic monocyclic, bicyclic or tricyclic heterocycle having one ring member, which contains one or more heteroatom ring members selected from nitrogen, oxygen or sulfur and C _1-6 alkyl, C _1-6 alkyloxy, halogen, hydroxy, optionally mono- or disubstituted amino, nitro, cyano, halo C ₁ on one or more carbon atoms _-6 alkyl, carboxyl, C _1-6 alkoxycarbonyl, C _3-7 cycloalkyl, optionally mono- or disubstituted Can be substituted by aminocarbonyl, methylthio, methylsulfonyl, aryl, Het ¹ and aromatic monocyclic, bicyclic or tricyclic heterocycles having 3 to 12 ring members Where the optional substituents on the amino function are C _1-6 alkyl, C _1-6 alkyloxy-A-, Het ¹ -A-, Het ¹ C _1-6 alkyl, Het ¹ C _1-6 alkyl -A-, Het ¹ oxy-A-, Het ¹ oxy C _1-4 alkyl-A-, aryl-A-, aryloxy-A-, aryloxy C _1-4 alkyl-A-, aryl C _1-6 Independently selected from alkyl-A-, C _1-6 alkyloxycarbonylamino-A-, amino-A-, amino C _1-6 alkyl and amino C _1-6 alkyl-A-; Wherein each of the amino groups can optionally be mono- or optionally di-substituted with C _1-4 alkyl, where A is as defined above.

As used herein, the term (═O) forms a carbonyl moiety with the carbon atom to which it is attached. The term (= O) forms a sulfoxide with the sulfur atom to which it is attached. The term (═O) ₂ forms a sulfonyl with the sulfur atom to which it is attached.

  As used herein, the term (= S) together with the carbon atom to which it is attached forms a thiocarbonyl moiety.

  As used herein above, the term “one or more” includes the possibility that all available atoms will be substituted as appropriate, preferably 1, 2 or 3. .

When any variable (eg, halogen or C _1-4 alkyl) occurs more than one time in any constituent, each definition is independent.

The term “prodrug” as used throughout the text means pharmacologically acceptable derivatives such as esters, amides and phosphates, and the biotransformation products of the resulting derivatives are defined in the compounds of formula (I). Active drug. Reference by Goodman and Gilman, which are generally described the prodrug ^{(The Pharmacological Basis of Therapeutics, 8} th ed., McGraw-Hill, Int.Ed.1992, "Biotransformation of Drugs", p.13-15) Is the content of this specification. Prodrugs of the compounds of the present invention are produced by modifying functional groups present in the compounds by routine treatment or by methods such that the modification is cleaved in vivo to yield the parent compound. Prodrugs are those in which a hydroxy group, such as a hydroxy group on an asymmetric carbon atom or an amino group, is conjugated to any group that cleaves to produce free hydroxyl or free amino, respectively, when the prodrug is administered to a patient. The compound of the present invention.

  Typical examples of prodrugs include, for example, WO 99/33795, WO 99/33815, WO 99/33793, the contents of which are incorporated herein by reference. No. pamphlet and International Publication No. 99/33792 pamphlet.

  Prodrugs are characterized by excellent water solubility and improved bioavailability, and are easily metabolized to active inhibitors in vivo.

  For therapeutic use, the salts of the compounds of formula (I) are those whose counterions are pharmaceutically or physiologically acceptable. However, salts with counterions that are not pharmaceutically acceptable may also find use, for example, in the preparation or purification of compounds of formula (I) that are pharmaceutically acceptable. All salts, whether pharmaceutically acceptable or unacceptable, are included within the scope of the present invention.

  The pharmaceutically acceptable or physiologically acceptable addition salt forms that the compounds of the present invention can form are suitable acids such as inorganic acids such as hydrohalic acids such as hydrochloric acid or hydrobromic acid; sulfuric acid. Hemisulfuric acid; nitric acid; acids such as phosphoric acid; or organic acids such as acetic acid, aspartic acid, dodecyl sulfuric acid, heptanoic acid, hexanoic acid, nicotinic acid, propanoic acid, hydroxyacetic acid, lactic acid, pyruvic acid, oxalic acid, malonic acid Succinic acid, maleic acid, fumaric acid, malic acid, tartaric acid, citric acid, methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, cyclamic acid, salicylic acid, p-aminosalicylic acid, pamoic acid, etc. It can be easily produced using acids.

  Conversely, the acid addition salt form can be converted to the free base form by treatment with a suitable base.

  Compounds of formula (I) containing acidic protons can also be converted to their nontoxic metal or amine addition salt forms by treatment with suitable organic and inorganic bases. Suitable base salt forms include, for example, ammonium salts, alkali and alkaline earth metal salts such as lithium, sodium, potassium, magnesium, calcium salts, salts with organic bases such as benzathine, N-methyl, -D-glucamine, It includes hydrabamine salts as well as salts with amino acids such as arginine, lysine and the like.

  Conversely, treatment with a suitable acid can convert the base addition salt form to the free acid form.

  The term “salt” also includes the hydrate and solvent addition forms that the compounds of the invention can form. Examples of such forms are eg hydrates, alcoholates and the like.

  N-oxide forms of the compounds are intended to include compounds of formula (I) in which one or several nitrogen atoms are oxidized to so-called N-oxides.

  The present compounds may also exist in their tautomeric form. Such forms although not explicitly indicated in the above formula are intended to be included within the scope of the present invention.

  The term stereochemical isomers of the compounds of the present invention used above are composed of the same atoms joined by the same permutation of bonds, but the incompatible and different three compounds that the compounds of the invention may have. -Define all possible compounds having a dimensional structure. Unless otherwise stated or indicated, the chemical name of a compound includes a mixture of all possible stereochemical isomers that the compound may have. The mixture can contain all diastereomers and / or enantiomers of the basic molecular structure of the compound. All stereochemical isomers of the compounds of the present invention, both in pure form or in admixture with each other, are intended to be included within the scope of the present invention.

  Pure stereoisomers of compounds and intermediates referred to herein are defined as isomers that are substantially free of other enantiomeric or diastereomeric forms of the same basic molecular structure of the compound or intermediate. . In particular, the term “stereoisomerically pure” refers to a stereoisomer excess from at least 80% (ie, a minimum of 90% of one isomer and a maximum of 10% of the other possible isomer). A compound or intermediate having a stereoisomer excess of 100% (ie 100% of one isomer and no other isomer), more particularly having a stereoisomer excess of 90% to 100%, Even more particularly, it relates to compounds or intermediates having a stereoisomer excess of 94% to 100% and most particularly having a stereoisomer excess of 97% to 100%. The terms “enantiomerically pure” and “diastereomerically pure” should be understood analogously, in which case the enantiomeric excess and the diastereomeric excess of the mixture in question respectively. About.

  Pure stereoisomers of the compounds and intermediates of the present invention can be obtained by application of methods known in the art. For example, enantiomers can be separated from each other by selective crystallization of their diastereomeric salts with optically active acids or bases. Examples thereof are tartaric acid, dibenzoyl tartaric acid, ditoluoyl tartaric acid and camphorsulfonic acid. Alternatively, enantiomers can be separated by chromatographic methods using a chiral stationary phase. The pure stereochemical isomers can also be derived from the corresponding pure stereochemical isomers of suitable starting materials, provided that the reaction occurs stereospecifically. Preferably, if a particular stereoisomer is desired, the compound will be synthesized by a stereospecific process. These methods will advantageously use enantiomerically pure starting materials.

  The diastereomeric racemates of formula (I) can be obtained separately by conventional methods. Suitable physical separation methods that can advantageously be used are, for example, selective crystallization and chromatography, for example column chromatography.

  It will be apparent to those skilled in the art that the compounds of formula (I) contain at least one asymmetric center and thus can exist as various stereoisomers. This irregular center is indicated by an asterisk (*) in the following formula.

  The absolute configuration of each asymmetric center that may be present in a compound of formula (I) can be indicated by stereochemical descriptors R and S, which R and S notation is described in Pure Appl. Chem. Corresponds to the rules described in 1976, 45, 11-30. The carbon atom marked with an asterisk (*) preferably has the R configuration.

  The present invention is also intended to include all isotopes of atoms occurring on the present compounds. Isotopes include those atoms having the same atomic number but different mass numbers. By way of general example and not limitation, isotopes of hydrogen include tritium and deuterium. Carbon isotopes include C-13 and C-14.

  Whenever used below, the terms “compound of formula (I)” or “present compound” or similar terms refer to compounds of general formula (I), their N-oxides, salts, stereoisomers, racemates. It is intended to include mixtures, prodrugs, esters and metabolites and their quaternized nitrogen analogs.

An interesting group of compounds is
R ₉ , R _10a and R _10b are each independently hydrogen, C _1-4 alkyloxycarbonyl, carboxyl, aminocarbonyl, mono- or di (C _1-4 alkyl) aminocarbonyl, C _3-7 cycloalkyl, C _2-6 alkenyl, C _2-6 alkynyl or optionally aryl, Het ¹ , Het ² , C _3-7 cycloalkyl, C _1-4 alkyloxycarbonyl, carboxyl, aminocarbonyl, mono- or di (C _1-4 Alkyl) aminocarbonyl, aminosulfonyl, C _1-4 alkyl S (O) _t , hydroxy, cyano, halogen or optionally mono- or disubstituted, wherein the substituent is C _1-4 alkyl, aryl, aryl _{C 1-4 alkyl, C 3-7} cycloalkyl, _{C 3 Cycloalkyl C 1-4} ^{alkyl, _{Het 1, Het 2, Het 1}} C 1-4 alkyl and ^Het 2 _{C 1-4 C 1-4} alkyl which may be substituted with amino selected from alkyl; Wherein R ₉ , R _10a and the carbon atom to which they are attached can also form a C _3-7 cycloalkyl group;
R _11b is hydrogen, C _3-7 cycloalkyl, C _2-6 alkenyl, C _2-6 alkynyl, aryl, Het ¹ , Het ² or optionally halogen, hydroxy, C _1-4 alkyl S (═O) _t , Aryl, C _3-7 cycloalkyl, Het ¹ , Het ² , optionally mono- or disubstituted, where the substituent is C _1-4 alkyl, aryl, aryl C _1-4 alkyl, C Substituted with amino selected from _3-7 cycloalkyl, C _3-7 cycloalkyl C _1-4 alkyl, Het ¹ , Het ² , Het ¹ C _1-4 alkyl and Het ² C _1-4 alkyl Can be C _1-4 alkyl;
Wherein R _11b can be attached to the rest of the molecule via a sulfonyl group;
t is zero, 1 or 2;
L is —C (═O) —, —O—C (═O) —, —NR ₈ —C (═O) —, —O—C _1-6 alkanediyl-C (═O) —, —NR _8- C _1-6 alkanediyl-C (═O) —, —S (═O) ₂ —, —O—S (═O) ₂ —, —NR ₈ —S (═O) ₂ , where In which either the C (═O) group or the S (═O) ₂ group is attached to the NR ₂ moiety;
R ₄ is hydrogen, C _1-4 alkyloxycarbonyl, carboxyl, aminocarbonyl, mono- or di (C _1-4 alkyl) aminocarbonyl, C _3-7 cycloalkyl, C _2-6 alkenyl, C _2-6 alkynyl Or optionally aryl, Het ¹ , Het ² , C _3-7 cycloalkyl, C _1-4 alkyloxycarbonyl, carboxyl, aminocarbonyl, mono- or di (C _1-4 alkyl) aminocarbonyl, aminosulfonyl, C _{1 -4} alkyl S (= O) _t , hydroxy, cyano, halogen and optionally mono- or disubstituted, where the substituent is C _1-4 alkyl, aryl, aryl C _1-4 alkyl, C _{3-7 cycloalkyl, C 3-7} cycloalkyl _{C 1-4} alkyl, H In _{^{t 1, Het 2, Het 1}} C 1-4 C 1-6 alkyl which may be substituted with alkyl and ^Het 2 _{C 1-4} 1 one or more substituents selected from amino selected from alkyl A compound of formula (I).

A particular group of compounds are compounds of formula (I) to which one or more of the following restrictions apply:
R ₁ is hydrogen, Het ¹ , Het ² , aryl, Het ¹ C _1-6 alkyl, Het ² C _1-6 alkyl, aryl C _1-6 alkyl, more particularly R ₁ is nitrogen, oxygen or sulfur Saturated or partially unsaturated monocyclic or bicyclic heterocycle having from 5 to 8 ring members optionally containing one or more heteroatom ring members selected from and optionally substituted Or is phenyl optionally substituted with one or more substituents;
Whether R ₂ is hydrogen;
L is —C (═O) —, —O—C (═O) —, —O—C _1-6 alkanediyl-C (═O) —, and more specifically, L is —O—C ( = O) - or _{-O-C 1-6} alkanediyl -C (= O) - and is, where either C (= O) group is attached to the NR ₂ moiety in each case;
Whether R ₃ is arylC _1-4 alkyl, in particular arylmethyl, more particularly phenylmethyl;
R ₄ is optionally substituted C _1-6 alkyl, especially unsubstituted C _1-6 alkyl or optionally aryl, Het ¹ , Het ² , C _3-7 cycloalkyl and optionally mono- or di- C, which can be substituted, wherein the substituent can be substituted with one or more substituents selected from C _1-4 alkyl, aryl, Het ¹ and amino selected from Het ¹ _{Is 1-6} alkyl;
Whether R ₅ is hydrogen or methyl;
R ₆ is hydrogen or methyl.

A special group of compounds are those in which R ₁ -L is Het ¹ -O—C (═O), Het ² -C _1-6 alkanediyl-O—C (═O), aryl-O—C _1-6 alkane. Compounds of formula (I) which are diyl-C (= O) or aryl-C (= O).

Compounds of formula (I) in which NR ₅ R ₆ is amino, monomethylamino or dimethylamino are also a special group of compounds.

Of particular interest are those where R ₁ is hydrogen, C _1-6 alkyl, C _2-6 alkenyl, aryl C _1-6 alkyl, C _3-7 cycloalkyl, C _3-7 cycloalkyl C _1-6 alkyl, aryl, Het ¹ , Het ¹ C _1-6 alkyl, Het ² , Het ² C _1-6 alkyl, in particular R ₁ is hydrogen, C _1-6 alkyl, C _2-6 alkenyl, aryl C _1-6 alkyl, C Compounds of formula (I) which are _3-7 cycloalkyl, C _3-7 cycloalkyl C _1-6 alkyl, aryl, Het ² , Het ² C _1-6 alkyl.

An interesting group of compounds are those in which R ₁ is hydrogen, C _1-6 alkyl, C _2-6 alkenyl, aryl C _1-6 alkyl, C _3-7 cycloalkyl, C _3-7 cycloalkyl-C _1-6 alkyl, Aryl, Het ¹ , Het ¹ C _1-6 alkyl, Het ² , Het ² C _1-6 alkyl; where Het ¹ has 5 or 6 ring members and is selected from nitrogen, oxygen or sulfur A formula (I) that is a saturated or partially unsaturated monocyclic heterocycle containing one or more heteroatom ring members and optionally substituted on one or more carbon atoms It is a compound of this.

Another interesting group of compounds are those compounds of formula (I) wherein L is —O—C _1-6 alkanediyl-C (═O) —.

  A preferred group of compounds are those in which the sulfonamide group is bonded to the benzoxazole group at the 6-position.

A suitable group of compounds is where R ₁ is aryl or arylC _1-6 alkyl; in particular, the aryl moiety of the definition of R ₁ is further substituted on one or more ring members, wherein each substituent The groups are C _1-4 alkyl, hydroxy, halogen, optionally mono- or di-substituted amino, optionally mono- or di-substituted amino C _1-4 alkyl, nitro and cyan. Preferably the substituent is selected from methyl, ethyl, chlorine, iodine, bromine, hydroxy and cyan, especially the aryl moiety contains 6 to 12 ring members, more particularly R ₁ The aryl moiety in the definition is a compound of formula (I) containing six ring members.

A suitable group of compounds is R ₁ is Het ² or Het ² C _1-6 alkyl, wherein Het ^{2 in} the definition of R ₁ is one or more each independently selected from nitrogen, oxygen and sulfur Containing more heteroatoms, in particular the Het ² moiety of the definition of R ₁ is further substituted on one or more ring members, wherein each substituent is C _1-4 alkyl, hydroxy, halogen, Optionally independently selected from amino and cyan which may be mono- or disubstituted; preferably the substituent is selected from the formula (I) selected from methyl, ethyl, chlorine, iodine, bromine, hydroxy, amino and cyan It is a compound of this.

In another group of compounds, R ₁ is Het ² or Het ² C _1-6 alkyl and L is —C (═O) —, —O—C (═O) —, —O—C _1-6. Alkanediyl-C (= O)-; in particular the Het ² moiety in the definition of R ₁ is an aromatic heterocycle having 5 or 6 ring members, each independently from nitrogen, oxygen or sulfur Containing one or more selected heteroatom ring members, more particularly the Het ² moiety is an aromatic heterocycle having 5 or 6 ring members, each independently of nitrogen, oxygen or sulfur. Or a compound of formula (I) containing two or more heteroatom ring members selected from:

A suitable group of compounds is that R ₁ is Het ¹ or Het ¹ C _1-6 alkyl; wherein Het ^{1 in} the definition of R ₁ is one or more independently selected from nitrogen, oxygen and sulfur Containing more heteroatoms; in particular the Het ¹ moiety of the definition of R ₁ is further substituted on one or more ring members, wherein each substituent is C _1-4 alkyl, hydroxy, halogen, Optionally independently selected from amino and cyan which can be mono- or disubstituted; preferably the substituent is selected from formula (I) selected from methyl, ethyl, chlorine, iodine, bromine, hydroxy, amino and cyan It is a compound of this.

Compounds suitable group, _{R 1} is ^Het 1 _{C 1-6} alkyl, Het ^1, wherein said Het ¹ in the definition of _{R 1} is monocyclic having 5 or 6 ring members, Where Het ¹ contains one or more heteroatoms independently selected from nitrogen, oxygen and sulfur; in particular, the Het ¹ moiety of the definition of R ₁ is further on one or more carbon atoms Substituted, wherein each substituent is independently selected from C _1-4 alkyl, hydroxy, halogen, optionally mono- or di-substituted amino and cyan; preferably the substituent is methyl And compounds of formula (I) selected from ethyl, chlorine, iodine, bromine, hydroxy, amino and cyanide.

A suitable group of compounds is where R ₁ is Het ¹ , where Het ¹ is bicyclic having 8-10 ring members, where Het ¹ is independently from nitrogen, oxygen and sulfur. Containing one or more heteroatoms selected from the above; in particular the Het ¹ moiety of the definition of R ₁ is further substituted on one or more carbon atoms, wherein each substituent is C _{1- 4} independently selected from alkyl, hydroxy, halogen, optionally mono- or disubstituted amino and cyan; preferably the substituents are methyl, ethyl, chlorine, iodine, bromine, hydroxy, amino and cyan In particular, the Het ¹ moiety is a compound of formula (I) containing two or more heteroatoms selected from nitrogen, sulfur and oxygen.

A suitable group of compounds is where R ₁ is Het ¹ , where Het ¹ is a saturated bicyclic group having 5-10 ring members, where Het ¹ is from nitrogen, oxygen and sulfur, respectively. Containing one or more independently selected heteroatoms, in particular the Het ¹ moiety of the definition of R ₁ is further substituted on one or more carbon atoms, wherein each substituent is C _1-4 independently selected from alkyl, hydroxy, halogen, optionally mono- or disubstituted amino and cyan; preferably the substituents are methyl, ethyl, chlorine, iodine, bromine, hydroxy, amino And in particular Het ¹ contains 5-8 ring members; in particular the Het ¹ moiety contains 6-8 ring members, where Het ¹ is nitrogen, sulfur And a compound of formula (I) containing two or more heteroatoms selected from oxygen.

An interesting group of compounds is that R ₁ is G or G—C _1-6 alkyl, where G is thiazolyl, imidazolyl, oxazolyl, oxadiazolyl, dioxazolyl, pyrazolyl, pyrazinyl, imidazolinonyl, quinolinyl, isoquinolinyl, indolyl, pyridazinyl , Pyridinyl, pyrrolyl, pyranyl, pyrimidinyl, furanyl, triazolyl, tetrazolyl, benzofuranyl, benzoxazolyl, isoxazolyl, isothiazolyl, thiadiazolyl, thiophenyl, tetrahydrofurofuranyl, tetrahydropyranofuranyl, benzothiophenyl, carbazolyl, imidazolonyl, oxazolonyl , Indolizinyl, triazinyl, quinoxalinyl, piperidinyl, piperazinyl, morpholinyl, thiamorpholinyl, pyrazinyl, Selected from enyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, β-carbolinyl, dioxanyl, dithianyl, oxolanyl, dioxolanyl, tetrahydrothiophenyl, tetrahydropyranyl, tetrahydropyranyl; where G is optionally benzofused Where G may optionally be further substituted on one or more ring members; preferably G is optionally substituted on one or more ring members. A compound of formula (I) selected from thiazolyl, imidazolyl, oxazolyl, oxadiazolyl, pyrazolyl, pyridinyl.

A suitable group of compounds are: R ₂ is hydrogen; R ₃ is alkylaryl; R ₄ is C _1-4 alkyl; in particular R ₂ is hydrogen; R ₃ is methylaryl; A compound of formula (I) wherein ₄ is isobutyl.

  A suitable group of compounds is the compound of formula (I) as a salt, wherein the salt is selected from trifluoroacetate, fumarate, chloroacetate and methanesulfonate.

  An interesting group of compounds are HIV species having at least one mutation in the HIV protease at a position selected from 10, 71 and 84 compared to the wild type sequence (eg M38432, K03455, gi327774); Formula (I) wherein the at least two mutations selected from 71 and 84 have a fold resistance within the range of 0.01 to 100 determined according to the methods described herein for an HIV species present in HIV protease. In particular, the compound has a fold resistance in the range of 0.1-100, more particularly in the range of 0.1-50, suitably in the range of 0.2-35. An interesting group of compounds are compound numbers 1-8, 10, 12-13, 18-21, 23-24, 34-37, 39, 42-50, 53, 56, 58-59 disclosed in the present invention. is there.

  A suitable group of compounds are compound numbers 1-3, 5-8, 18, 21, 23, 35, 46, 48-50, 53, 59 and 61 disclosed in the present invention.

  The invention relates to a pharmaceutical comprising a solid dispersion comprising (a) a compound as claimed in any of claims 1 to 10, (b) one or more pharmaceutically acceptable water-soluble polymers. It also relates to a pharmaceutical composition. In particular, the compound is selected from compound numbers 1 to 3, 5 to 8, 18, 21, 23, 35, 46, 48 to 50, 53, 59 and 61. Conveniently, the water-soluble polymer includes hydroxypropyl methylcellulose, polyvinylpyrrolidone copolymer (PVP-VA) with vinyl acetate.

  Compounds having interesting pharmacokinetic properties are compounds of formula (I) containing at least one substituent independently selected from thiazole, imidazole and pyridine.

  The compounds of formula (I) are generally described in WO 95/06030 pamphlet, WO 96/22287 pamphlet, WO 96/28418 pamphlet, WO 96/28463 pamphlet, WO It can be produced using methods similar to those described in the 96/28464 pamphlet, the WO 96/28465 pamphlet and the WO 97/18205 pamphlet.

  Specific reaction methods for the preparation of this compound are described below. In the manufacture described below, the reaction product can be isolated from the medium and further purified if necessary according to methods generally known in the art, such as extraction, crystallization, trituration and chromatography.

  A 2-amino-6-chlorosulfonylbenzoxazole derivative (intermediate a-2) was prepared according to the method described in EP-A-0,445,926.

Intermediate a-3, prepared according to the method described in WO 97/18205 and also depicted in Scheme B, is prepared by reacting a base such as triethylamine in a reaction inert solvent such as dichloromethane. Intermediate a-4 was prepared by reacting with intermediate a-2 in the presence at low temperature, for example at 0 ° C. The Boc group in intermediate a-3 is a protected tert-butyloxycarbonyl group. It can simply be replaced by other suitable protecting groups such as phthalimide or benzyloxycarbonyl. Depending on the nature of the amino group at the 2-position of benzoxazole in a suitable solvent such as a mixture of ethanol and dioxane, an intermediate a with an acid such as hydrochloric acid in isopropanol or with trifluoroacetic acid -4 can be deprotected, thus producing intermediate a-5. The intermediate a-5 is prepared in the presence of a base such as triethylamine (in the case of an alcohol that produces a carbamate) and optionally 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (EDC) and 1-hydroxy Intermediate of formula R ₁ -L- (leaving group) in the presence of an alcohol such as benzotriazole (HOBT) (in the case of a carboxylic acid producing an amide) or tert-butanol and in a suitable solvent such as dichloromethane. Can be further reacted with the body; thus forming intermediate a-6. In particular an intermediate of formula _R 1 -C (= O) -OH are suitable to further react with an intermediate a-5.

In a convenient preparation of compounds of formula (I) wherein both R ₅ and R ₆ are hydrogen, the compound is analogous to the method described in Scheme A and one of R ₅ or R ₆ Can be prepared by replacing with a suitable protecting group such as an acetyl or alkyloxycarbonyl group. In such a case, deprotection can be performed simultaneously with deprotection of the nitrogen atom on the left side of the molecule.

  The intermediates and starting materials used in the above production are known compounds, others can be produced according to methods for producing the compounds or similar compounds known in the art.

Intermediate b-2 corresponding to intermediate a-3 in Scheme A can be prepared by adding an amine of formula H ₂ N—R ₄ to intermediate b-1 in a suitable solvent such as isopropanol. it can.

  In Scheme B, the enantiomerically pure compound of formula b-2 is obtained only when b-1 is enantiomerically pure. If b-1 is a mixture of stereoisomers, b-2 will also consist of a mixture of stereoisomers.

One specific example of the preparation of an intermediate of formula R ₁ -L- (leaving group) used in Scheme A is depicted in Scheme C.

  Compounds of formula (I) can also be converted to the corresponding N-oxide form according to methods known in the art for converting trivalent nitrogen to its N-oxide form. The N-oxidation reaction can generally be carried out by reacting the starting material of formula (I) with a suitable organic or inorganic peroxide. Suitable inorganic peroxides include, for example, hydrogen peroxide, alkali metal or alkaline earth metal peroxides such as sodium peroxide, potassium peroxide; suitable organic peroxides include peroxy acids such as benzene carbo Peroxo acids or halo-substituted benzene carboperoxo acids such as 3-chloro-benzene carboperoxo acids, peroxoalkanoic acids such as peroxoacetic acid, alkyl hydroperoxides such as tert-butyl hydroperoxide may be included. Suitable solvents are, for example, water, lower alkanols such as ethanol, hydrocarbons such as toluene, ketones such as 2-butanone, halogenated hydrocarbons such as dichloromethane and mixtures of such solvents.

  Thus, in animals, preferably in mammals and in particular in humans, the compounds can be used as drugs as such, in admixture with one another or in the form of pharmaceutical preparations.

  The invention further relates to pharmaceutical preparations which contain at least one effective dose of the compound of formula (I) as active ingredient in addition to the usual pharmaceutically non-toxic excipients and auxiliaries. The pharmaceutical preparations usually contain from 0.1 to 90% by weight of the compound of formula (I). The pharmaceutical preparations can be prepared in a manner known per se to those skilled in the art. For this purpose, at least one compound of formula (I) is combined with one or more solid or liquid pharmaceutical excipients and / or auxiliaries and, if desired, other pharmaceutical activities. It can be combined with the compound to form a suitable dosage form or dosage form which can then be used as a medicament in human or veterinary medicine.

  The medicament containing the compound according to the invention can be administered orally, parenterally, for example intravenously, rectally, by inhalation or topically, the preferred administration should be treated in individual cases, for example Depends on the specific path of failure. Oral administration is preferred.

  A person skilled in the art, based on his expertise, is accustomed to auxiliaries suitable for the desired pharmaceutical preparation. In addition to solvents, gel-forming agents, suppository bases, tablet adjuvants and other active compound carriers, antioxidants, dispersants, emulsifiers, antifoaming agents, flavor correctors, preservatives, solubilizers, depot effects Agents, buffer substances or colorants to achieve this are also useful.

  Because of their favorable pharmacological properties, particularly their activity against multidrug resistant HIV protease enzymes, the compounds of the invention are useful in the treatment of patients infected with HIV and for the prevention of these patients. In general, the compounds of the present invention may be useful in the treatment of warm-blooded animals infected with viruses whose presence is mediated by or dependent on protease enzymes. Conditions that can be prevented or treated with the compounds of the invention, particularly those associated with HIV and other pathogenic retroviruses, include AIDS, AIDS-related syndromes (ARC), progressive systemic lymphadenopathy ( PGL) and chronic CNS diseases caused by retroviruses such as HIV-mediated dementia and multiple sclerosis.

  Accordingly, the compounds of the present invention or any subgroup thereof can be used as agents for the above conditions. The method of use or treatment as a medicament includes systemic administration of an amount effective to control a condition associated with HIV and other pathogenic retroviruses, particularly HIV-1, to an HIV-infected patient. Ultimately, the compounds of the invention can be used in the manufacture of a medicament useful for the treatment of conditions associated with HIV and other pathogenic retroviruses, particularly for the treatment of patients infected with multi-drug resistant HIV viruses.

  In a preferred embodiment, the present invention relates to a compound of formula (I) or any of them in the manufacture of a medicament for the treatment or control of a multidrug resistant retroviral infection in mammals, in particular an infection or disease associated with HIV-1 infection. Regarding the use of subgroups. Thus, the present invention provides a method of treating a disease associated with a retroviral infection or a multidrug resistant retroviral infection comprising administering to a mammal in need thereof an effective amount of a compound of formula (I) or a subgroup thereof. Also related.

  In another preferred embodiment, the present invention relates to formula (I) or any sub thereof in the manufacture of a medicament for inhibiting a retroviral protease in a mammal infected with a multidrug resistant retrovirus, in particular an HIV-1 virus. Regarding the use of groups.

  In another preferred embodiment, the invention relates to the use of formula (I) or any of its subgroups in the manufacture of a medicament for the inhibition of multidrug resistant retroviral replication, in particular HIV-1 replication.

  The compounds of the present invention may also find use in inhibiting in vitro samples that contain or are expected to be exposed to HIV. Thus, the compounds can be used for the inhibition of HIV present in a body fluid sample that contains, appears to contain, or appears to be exposed to HIV.

  Moreover, the combination of an antiretroviral compound and the compound of this invention can be used as a chemical | medical agent. Thus, the present invention provides (a) a compound of the invention and (b) as a combined preparation for simultaneous, separate or sequential use in the treatment of retroviral infections, particularly in the treatment of infections with multidrug resistant retroviruses. It also relates to products containing other antiretroviral compounds. Thus, for the control or treatment of HIV infection or infection and diseases associated with HIV, such as acquired immune deficiency syndrome (AIDS) or AIDS-related syndrome (ARC), the compounds of the present invention can be used, for example, as binding inhibitors such as dextran. Sulfate, suramine, polyanions, soluble CD4, PRO-542, BMS-806; fusion inhibitors such as T20, T1249, 5-helix, D-peptide, ADS-J1; co-receptor Binding inhibitors, such as AMD 3100, AMD-3465, AMD7049, AMD3451 (Bicyclams), TAK 779; SHC-C (SCH351125), SHC-D, PRO-140RT inhibitors, such as foscarnet and Prodrugs; nucleoside RTIs such as AZT, 3TC, DDC, DDI, D4T, Abacavir, FTC, DAPD, dOTC, DPC817; nucleotide RTIs such as PMEA, PMPA (tenofovir); NNRTIs e. ), Delavirdine, efavirenz, 8 and 9-Cl TIBO (tivirapine)), loviride, TMC-125, dapivirine, C782, UK78, U (Capravirine), DPC961, DPC963, DPC082, DPC083, Karano DeA (calanolide A), SJ-3366, TSAO, 4 ″ -deaminated TSAO, MV150, MV026048; RNAse H inhibitors such as SP1093V, PD126338; TAT inhibitors such as RO-5-3335, K12, K37; Integrase inhibitors such as L 708906, L 731988, S-1360; protease inhibitors such as amprenavir and prodrugs GW908, ritonavir, nelfinavir, saquininavir, saquininavir ), Lopinavir, parinavir, BMS 186316, atazanavir avir), DPC 681, DPC 684, tipranavir, AG1776, mozenavir, GS3333, KNI-413, KNI-272, L754425, L756425, LG161317, PD17383PD, 72173PD, PD17383PD 140135, TMC114, maslinic acid, U-14690; glycosylation inhibitors such as castanospermine, deoxynojirimycin can be co-administered.

  The combination can provide a synergistic effect in some cases, thereby preventing, substantially reducing or completely eliminating viral infectivity and its associated symptoms.

  For the improvement, control or elimination of HIV infection and its symptoms, the compounds of the present invention may be combined with immunomodulators (eg bropirimine, anti-human alpha interferon antibodies, IL-2, methionine enkephalin, interferon alpha, HE-2000. And naltrexone), antibiotics (eg, pentamidine isothiolate), cytokines (eg, Th2), cytokine modulators, chemokines or their receptors (eg, CCR5) or hormones (eg, growth hormone) Combinations can also be administered. Such combination therapies in various formulations can be administered simultaneously, separately or sequentially. Alternatively, such combinations can be administered as a single formulation, in which case the active ingredients are released from the formulation simultaneously or separately.

  The compounds of the present invention can also be administered in combination with a modulator of metabolism following application of the drug to the patient. These modulators include compounds that interfere with metabolism in cytochromes, such as cytochrome P450. Some modulators inhibit cytochrome P450. Several isoenzymes of cytochrome P450 are known to exist, one of which is cytochrome P450 3A4. Ritonavir is an example of a regulator of metabolism through cytochrome P450. Such combination therapies in various formulations can be administered simultaneously, separately or sequentially. Alternatively, such combinations can be administered as a single formulation, in which case the active ingredients are released from the formulation simultaneously or separately. Such modulators can be administered at the same or different ratio as the compounds of the present invention. Preferably, the weight ratio of such modulator to the compound of the invention (modulator: compound of the invention) is 1: 1 or lower, more preferably the ratio is 1: 3 or lower, suitably The ratio is 1:10 or lower, more suitably the ratio is 1:30 or lower.

  For oral dosage forms, the compounds of the invention are mixed with suitable additives, such as excipients, stabilizers or inert diluents, and suitable dosage forms, such as tablets, coated tablets, hard Capsule, aqueous, alcoholic or oily solution. Examples of suitable inert carriers are gum arabic, magnesia, magnesium carbonate, potassium phosphate, lactose, glucose or starch, in particular corn starch. In this case, the preparation can be carried out as both dry and wet granules. Suitable oily excipients or solvents are vegetable or animal oils such as sunflower oil or liver oil. Suitable solvents for aqueous or alcoholic solutions are water, ethanol, sugar solutions or mixtures thereof. Polyethylene glycols and polypropylene glycols are also useful as additional auxiliaries for other dosage forms.

  For subcutaneous or intravenous administration, the active compounds are brought into solutions, suspensions or emulsions, if desired, together with the usual substances therefor, such as solubilizers, emulsifiers or further auxiliaries. The compound of formula (I) can be lyophilized and the resulting lyophilizate can be used, for example, for the preparation of injection or infusion preparations. Suitable solvents are, for example, water, saline or alcohols such as ethanol, propanol, glycerol and also sugar solutions such as glucose or mannitol solutions or also mixtures of the various solvents mentioned above.

  Pharmaceutical formulations suitable for administration in the form of an aerosol or spray are, for example, pharmaceutically acceptable solvents, such as ethanol or water, of the compounds of formula (I) or physiologically acceptable salts thereof. Alternatively, it is a solution, suspension or emulsion in a mixture of such solvents. If necessary, the formulation can also contain other pharmaceutical auxiliaries such as surfactants, emulsifiers and stabilizers and propellants. Such preparations usually contain the active compound in a concentration of about 0.1 to 50% by weight, in particular about 0.3 to 3% by weight.

  In order to enhance the solubility and / or stability of the compound of formula (I) in the pharmaceutical composition, it may be advantageous to use α-, β- or γ-cyclodextrins or their derivatives. Co-solvents such as alcohols can also improve the solubility and / or stability of the compound of formula (I) in the pharmaceutical composition. In preparing aqueous compositions, the addition salts of the compounds are clearly more suitable due to their improved water solubility.

Suitable cyclodextrins are α-, β-, γ-cyclodextrins (CDs) or one or more of the hydroxy groups of the anhydroglucose unit of the cyclodextrin is C _1-6 alkyl, especially methyl, ethyl or isopropyl Ethers and mixed ethers substituted with, for example, randomly methylated β-CD; hydroxy C _1-6 alkyl, especially hydroxyethyl, hydroxypropyl or hydroxybutyl; carboxy C _1-6 alkyl, C _1-6 alkyl-carbonyl, especially acetyl; C _1-6 alkyloxycarbonyl C _1-6 alkyl or carboxy C _1-6 alkyloxy C _1-6 alkyl, especially carboxymethoxypropyl or carboxy Ethoxypropyl; C _1-6 alkylcarbonyloxy C _1-6 alkyl, especially those ethers and mixed ethers substituted with 2-acetyloxypropyl. Of particular note as complexing agents and / or solubilizers are β-CD, randomly methylated β-CD, 2,6-dimethyl-β-CD, 2-hydroxyethyl-β-CD, 2 -Hydroxyethyl-γ-CD, 2-hydroxypropyl-γ-CD and (2-carboxymethoxy) propyl-β-CD and especially 2-hydroxypropyl-β-CD (2-HP-β-CD).

  The term mixed ether denotes a cyclodextrin derivative in which at least two cyclodextrin hydroxy groups are etherified with different groups, for example with hydroxy-propyl and hydroxyethyl.

  An interesting method for preparing the present compounds in combination with cyclodextrins or their derivatives is described in EP 721,331. The formulations described there are for antibacterial and fungal active ingredients, but they are equally interesting for the preparation of the compounds according to the invention. The preparations described therein are particularly suitable for oral administration, as antibacterial / fungal agents as active ingredients, sufficient amounts of cyclodextrins or their derivatives as solubilizers, as bulk liquid carriers An aqueous acidic medium and an alcoholic co-solvent that greatly simplifies the preparation of the composition. The preparation can also be made tasteful by adding pharmaceutically acceptable sweeteners and / or flavorings.

  Other simple methods for enhancing the solubility of the compounds of the invention in pharmaceutical compositions are WO 94/05263, WO 98/42318, EP 499,299. And the pamphlet of International Publication No. WO 97/44014, all of which are incorporated herein by reference.

  More particularly, a therapeutically effective amount of particles comprising (a) a compound of formula (I) and (b) a solid dispersion comprising one or more pharmaceutically acceptable water-soluble polymers. The compound can be prepared in a pharmaceutical composition comprising.

  The term “solid dispersion” includes at least two components, where one component is more or less uniformly dispersed throughout one or more other components (relative to the liquid or gaseous state). Defines the system in. Where the component dispersion is such that the system is chemically and physically uniform throughout or homogeneous, or consists of a single phase defined by thermodynamics, such a solid dispersion is It is called “solid solution”. Solid solutions are a preferred physical system because the components therein are usually readily bioavailable to the organism to which they are administered.

  The term “solid dispersion” also includes dispersions that are less uniform throughout than solid solutions. Such dispersions are not chemically and physically uniform throughout or contain more than one phase.

  The water-soluble polymer in the particles is conveniently 1-100 mPa.s when dissolved in a 2% aqueous solution at 20 ° C. It is a polymer having an apparent viscosity of s.

  A preferred water-soluble polymer is hydroxypropyl methylcellulose or HPMC. HPMC having a methoxy substitution degree of about 0.8 to about 2.5 and a hydroxypropyl molar substitution of about 0.05 to about 3.0 are generally water soluble. The degree of methoxy substitution refers to the average number of methyl ether groups present per anhydroglucose unit of the cellulose molecule. Hydroxy-propyl molar substitution refers to the average number of moles of propylene oxide reacted with each anhydroglucose unit of the cellulose molecule.

  The particles defined above can be prepared by first preparing a solid dispersion of the components and then optionally grinding or grinding the dispersion. There are various methods for the preparation of solid dispersions, including melt-extrusion, spray-drying and solution-evaporation, with melt-extrusion being preferred.

  It may be more convenient to prepare the compound in the form of nanoparticles with a surface modifier adsorbed on the surface in an amount sufficient to maintain an effective average particle size of less than 1000 nm. Useful surface modifiers would include those that physically adhere to the surface of the antiretroviral drug but do not chemically bind to the antiretroviral drug.

  Suitable surface modifiers can preferably be selected from known organic and inorganic pharmaceutical excipients. Such excipients include various polymers, low molecular weight oligomers, natural products and surfactants. Preferred surface modifiers include nonionic and anionic surfactants.

  Yet another interesting method of preparation of the compound is to apply the pharmaceutical composition in which the compound is incorporated into a hydrophilic polymer and the mixture as a coated film on a number of small beads, thus making it easy to produce. And obtaining a composition with excellent bioavailability suitable for the preparation of pharmaceutical dosage forms for oral administration.

  The beads include (a) a central round or spherical core, (b) a hydrophilic polymer and antiretroviral drug coating film, and (c) a seal-coating polymer layer.

  A suitable material for use as a bead core is a manifold, provided that the material is pharmaceutically acceptable and has suitable dimensions and stiffness. Examples of such materials are polymers, inorganic substances, organic substances and sugars and their derivatives.

  The route of administration may depend on the patient's condition, co-medication, etc. performed in parallel.

  Another aspect of the present invention is to formula (I) in an amount effective for use as a standard or reagent in a test or assay to determine the ability of a potential agent to inhibit HIV protease, HIV growth or both. ) Or a container containing the compound. This aspect of the invention can find its use in drug discovery programs.

The compounds of the present invention can be used in phenotypic resistance monitoring assays, such as known recombinant assays, in the clinical treatment of resistance-expressing diseases such as HIV. A particularly useful resistance monitoring system is the recombination assay known as Antivirogram ^™ . Antivirogram ^™ is a highly automated, high throughput second generation recombination assay that can measure susceptibility to the compounds of the present invention, particularly viral susceptibility. (Hertogs K, de Bethune MP, Miller V et al. Antimicrob Agents Chemother, 1998; 42 (2): 269-276, the contents of which are incorporated herein by reference).

  Interestingly, the compounds of the present invention can include chemically reactive moieties that can be covalently bound to localized sites, and the compounds can have improved tissue retention and half-life. As used herein, the term “chemically reactive group” refers to a chemical group capable of forming a covalent bond. The reactive group is generally stable in an aqueous environment, usually carboxy, phosphoryl or simply an acyl group as an ester or mixed anhydride or an imidate or maleimidate, for example at a target site on a blood component such as albumin. A covalent bond can be formed with a functional group such as an amino group, hydroxy or thiol. The compounds of the present invention can be linked to maleimides or derivatives thereof to form conjugates.

The dosage of the compound to be administered, or one or more physiologically acceptable salts thereof, will depend on the individual case and should usually be adapted to the condition of each case for optimal effect. is there. Thus it will of course depend on the frequency of administration and the potency and duration of action of the compound used in each case for treatment or prevention, but the nature and severity of the infection and symptoms and the sex of the human or animal to be treated , Age, weight, parallel dosing and responsiveness, and whether treatment is urgent or prophylactic. Usually, for administration to a patient weighing about 75 kg, the daily dosage of the compound of formula (I) is 1 mg to 3 g, suitably 1 mg to 1 g, preferably 3 mg to 0.5 g, more preferably 5 mg to 300 mg. The dosage can be administered in the form of a respective dosage or can be divided into several dosages, for example 2, 3 or 4 respective dosages.
Experimental part

Preparation of Compound 3 To a mixture of 300 mg 5-hydroxymethylthiazole and 789 mg triethylamine in dichloromethane was added 735 mg DSC (N, N′-disuccinimidyl carbonate). After stirring for 6 hours at room temperature, the organic phase was washed with saturated bicarbonate solution. After drying over MgSO ₄ , the solvent is filtered, then 525 mg of triethylamine and 1.1 g of intermediate a-5 [R ₂ , R ₅ and R ₆ are hydrogen and R ₄ = —CH ₂ —CH ( CH ₃ ) ₂ ] was added. After stirring overnight, the solvent was evaporated under vacuum. Purification by column chromatography gave 800 mg of compound 3.

Preparation of compound 5 1 g of intermediate a-5 in 120 ml dichloromethane [R ₂ , R ₅ and R ₆ are hydrogen, R ₄ = —CH ₂ —CH (CH ₃ ) ₂ ], 78 mg HOBT (A mixture of hydroxybenzotriazole, 488 mg EDC and 416 mg 2- (2,6-dimethylphenoxy) acetic acid was stirred overnight at room temperature. The reaction mixture was then washed with 5% HCl, saturated NaHCO ₃ solution and brine. The layers were separated, dried, the solvent was evaporated and the residue was purified by column chromatography to give 1.3 g of compound 5 in 98% yield.

Preparation of Compound 7 Mixture of 259 mg of intermediate a-5 [R ₂ , R ₅ and R ₆ are hydrogen, R ₄ = —CH ₂ —CH (CH ₃ ) ₂ ] and 60 mg of triethylamine in dichloromethane 163 mg of 1-[[[[[(3R, 3aS, 6aR) -hexahydrofuro [2,3-b] furan-3-yl] oxy] carbonyl] oxy] -2,5-pyrrolidine-dione (International Publication No. 9967417 pamphlet) was added. The mixture was stirred at room temperature for 12 hours. After evaporation of the dichloromethane under reduced pressure, the crude product was purified on silica to give 340 mg of compound 7 (96%).

Preparation of compound 8 and salt a) 289 mg of intermediate a-5 in dichloromethane [R ₂ and R ₅ are hydrogen, R ₆ is CH ₃ and R ₄ = —CH ₂ —CH (CH ₃ ) ₂ 176 mg of 1-[[[[[(3R, 3aS, 6aR) -hexahydrofuro [2,3-b] furan-3-yl] oxy] carbonyl] oxy] -2 in a mixture of 70 mg of triethylamine. , 5-pyrrolidine-dione (described in WO 9967417 pamphlet) was added. The mixture was stirred at room temperature for 12 hours. After evaporating dichloromethane under reduced pressure, the crude product was purified on silica to give 343 mg of compound 8 (94%).
b) 1 g of compound 8 was dissolved in tetrahydrofuran with heating. 160 mg of methane-sulfonic acid in tetrahydrofuran was added. After 5 minutes, precipitation was observed. After stirring for 30 minutes and cooling to room temperature, the precipitate was filtered. Drying under reduced pressure gave 889 mg of compound 48 (77%).

  Hydrochloride (Compound 49) and fumarate (Compound 50) were prepared in a similar manner.

Preparation of compound 45 a) 1.7 g of 4-nitropyridine-3,5-lutidine N-oxide (as described in WO 99/10326 or European Patent Application 0103 553 A1) Preparation), a mixture of 2.1 g ethyl glycolate and 1.4 g potassium carbonate was warmed to 60 ^° for 4 h (h). The crude material was purified directly by column chromatography to give 1.8 g (80%) of 3,5-dimethyl-pyridine-N-oxide-4-oxyacetate. The compound was stirred in 20 ml ethanol / water 1/1 and 1.4 g potassium carbonate for 1 hour. A solid formed and was filtered to give 1.5 g (95%) of 2,4-dimethyl-pyridine-N-oxide-3-oxy-acetic acid (see Scheme C).
b) 0.43 g of intermediate a-5 [R ₂ , R ₅ and R ₆ are hydrogen in 10 ml N, N-dimethylformamide, R ₄ = —CH ₂ —CH (CH ₃ ) ₂ ], A mixture of 50 mg HOBT (hydroxybenzotriazole), 197 mg EDC and 197 mg 3,5-dimethyl-pyridine-N-oxide-4-oxy-acetic acid was stirred at room temperature overnight. The solvent was evaporated and then washed with 5% HCl, saturated NaHCO ₃ solution and brine. The organic layer was separated, dried and evaporated. The residue was purified by column chromatography to give 300 mg of compound 45 (50%).

Preparation of Compound 46 A mixture of 250 mg of Compound 45, 250 mg of palladium hydroxide and 1 g of ammonium formate in 10 ml of methanol was stirred at reflux overnight. The crude product was filtered over decalite and the filtrate was evaporated and purified on column chromatography to give 72 mg (28%) of compound 46.

  A mixture of 2.5 g 2-aminophenol (7-1) and 20 ml ethyl acetate was heated to 45 ° C. To the mixture was added 3 g of cyanogen bromide. The mixture was stirred at 45-50 ° C. for 12 hours. After cooling to room temperature, 1.5 g of sodium hydroxide in 15 ml of water was added. The organic layer was separated and washed with brine until neutral pH. Toluene (5 ml) was added and the solvent removed to give 2.71 g (88%) of 2-aminobenzoxazole (7-2).

  7.5 ml of chlorosulfonic acid was stirred at room temperature under an inert atmosphere (nitrogen). 5 g of 2-aminobenzoxazole (7-2) was added little by little. The temperature was kept at 30-60 ° C during the addition of 7-2. The mixture was heated to 80 ° C. for 2 hours. While maintaining the temperature at 65 ° C., 5.3 g of thionyl chloride was added dropwise. The mixture was stirred for 2 hours. After cooling to 0 ° C., 10 ml of ethyl acetate and 10 ml of sodium carbonate solution (1N) were added. The organic layer was separated from the aqueous layer and the aqueous layer was extracted with ethyl acetate. The combined organic layers were dried over calcium chloride to give 7.8 g (90%) of 2-amino-6-chlorosulfonylbenzoxazole (7-3).

  A mixture of 1 g sodium methoxide and 10 ml toluene was stirred at 0 ° C. under nitrogen atmosphere. While maintaining the temperature at 5 to 10 ° C., a mixture of 1.9 g of methyl chloroacetate (8-1) and 1.1 g of methyl formate was added dropwise. The mixture was stirred at 0 ° C. for 2 hours. After washing with water, the organic layer was dried and evaporated under reduced pressure to give 2-chloro-3-oxo-propionic acid methyl ester (8-2).

  A mixture of 2.4 g 2-chloro-3-oxo-propionic acid methyl ester (8-2), 20 ml water and 1.75 g thiourea was refluxed for 2 hours. The mixture was cooled to room temperature and 0.25 g norit was added and filtered. A solution of 2.5N sodium hydroxide was added to the filtrate to neutral pH. Filtration gave 1.23 g (44%) of 2-amino-thiazole-5-carboxylic acid methyl ester (8-3).

  A mixture of 2.15 g isoamyl nitrate and 10 ml dioxane was stirred at 80 ° C. under a nitrogen atmosphere. A solution of 1.23 g 2-aminothiazole-5-carboxylic acid methyl ester (8-3) in 20 ml dioxane was added dropwise. The mixture was refluxed for 2 hours. After cooling to room temperature, 30 ml of ethyl acetate was added. The mixture was washed with brine, dried and the solvent was evaporated under reduced pressure. The crude product was purified on silica to give 0.54 g (48%) of thiazole 5-carboxylic acid methyl ester (8-4).

  A mixture of 0.54 g of thiazole 5-carboxylic acid methyl ester (8-4) and 10 ml of tetrahydrofuran (THF) was stirred at 0 ° C. under a nitrogen atmosphere. A mixture of 0.16 g lithium aluminum hydride and 5 ml ether was added dropwise. After 1 hour at 0 ° C., water and 20% sodium hydroxide were added and stirred for 30 minutes (min). The mixture was filtered over decalite and the solvent removed by azeotropic distillation with toluene to give 0.3 g (69%) thiazol-5-yl-methanol (8-5).

  A mixture of 1.15 g thiazol-5-yl-methanol (9-1) and 1.2 g triethylamine (TEA) in 25 ml dichloromethane (DCM) was stirred at room temperature under nitrogen atmosphere. 2.56 g of N, N'-disuccinimidyl carbonate was then added and the resulting mixture was stirred for 10-15 minutes. The solution was stirred for an additional 2 hours. The resulting intermediate (9-2) was used directly in the subsequent reaction with amine (9-3). The salt can be used in place of the amine.

  2 g of triethylamine and 5 g (9-3) of amine were added to 40 ml of dichloromethane, and the resulting mixture was stirred at room temperature. Subsequently, a part of the solution containing 9-2 was dropped. The reaction mixture was stirred at room temperature for 2 hours. The reaction mixture was washed with water and then dried to obtain compound (9-4).

  Similar to any one of the above examples, the following compounds were prepared:

Antiviral analysis:
The compounds of the invention were tested for anti-viral activity in cellular assays. The assay showed that these compounds show potent anti-HIV activity against wild type laboratory HIV strain (HIV-1 strain LAI). The cell assay was performed according to the following method.
Cell assay experiment:
HIV- or mock-infected MT4 cells were incubated for 5 days in the presence of various concentrations of inhibitors. At the end of the incubation period, all HIV-infected cells in standard culture in the absence of inhibitor were killed by replicating virus. Cell viability is measured by measuring the concentration of MTT, a yellow water-soluble tetrazolium dye, that is converted only into mitochondria of viable cells into formazan that is insoluble in purple water. When the resulting formazan crystals are solubilized with isopropanol, the absorbance of the solution is monitored at 540 nm. The value is directly related to the number of viable cells remaining in culture upon completion of the 5 day incubation. The inhibitory activity of the compounds was monitored on virus-infected cells and expressed as EC ₅₀ and EC ₉₀ . These values indicate the amount of compound needed to protect 50% and 90% of the cells from the cytopathic effect of the virus, respectively. Compound toxicity was measured on mock-infected cells and expressed as CC ₅₀ , which indicates the concentration of compound required to inhibit cell growth by 50%. The selectivity index (SI) (ratio CC ₅₀ / EC ₅₀ ) is an indicator of the selectivity of the inhibitor's anti-HIV activity. Whenever a result is reported as, for example, a pEC ₅₀ or pCC ₅₀ value, the result is expressed as the negative logarithm of the result expressed as an EC ₅₀ or CC _50, respectively.

The SI for the compounds investigated ranged from values higher than 10 to values higher than 10,000.
Antiviral scope:
As the emergence of drug resistant HIV strains has increased, the compounds were tested for their titer against clinically isolated HIV strains carrying several mutations (Tables 2 and 3). . These mutations are associated with resistance to protease inhibitors, resulting in viruses that exhibit varying degrees of phenotypic cross-resistance to currently commercially available drugs such as saquinavir, ritonavir, nelfinavir, indinavir and amprenavir. .

result:
The fold resistance (FR), defined as FR = EC ₅₀ (mutant strain) / EC ₅₀ (HIV-1 strain LAI), was determined as a measure of the broad activity of the compounds. Table 3 shows the results of antiviral testing for fold resistance. As can be seen in this table, the compounds are effective in inhibiting a wide range of mutants: column A: FR value for mutant A, column B: FR for mutant B, column C: for mutant C FR, D column: FR for mutant strain D, E column: FR for mutant strain E, F column: FR for mutant strain F. Toxicity (Tox) is expressed as pCC ₅₀ values determined using mock-transfected cells. The WT column shows the pEC50 value for the wild type HIV-LAI strain.

Caco-2 Permeability Assay for Intestinal Absorption Permeability of various compounds was determined by Augustijns et al. (Augustijns et al. (1998). Int. J. of Pharm, 166, 45-54), which was evaluated according to the Caco-2 test plan described in that method, with Caco-2 at cell passage numbers of 32-45. Cells are grown for 21-25 days in 24-well transwell cell culture plates. The integrity of the cell monolayer is examined by measuring transepithelial electrical resistance (TEER). The test is performed at a pH of 7.4 and a donor compound concentration of 100 μM. Serial samples are taken at the receptor side and the cumulative amount and apparent permeability are calculated.
Equilibrium solubility in simulated gastrointestinal solutions under water soluble thermodynamic conditions at various pH levels is an excellent measure of the solubility profile of the compound in various parts of the stomach and intestine. Simulated gastric fluid (SGF) (no pepsin) is set to a pH of 1.5. Simulated intestinal fluid (SIF) (without bile salts) is set to pH 5, pH 6.5, pH 7 and pH 7.5. The experimental design uses 98-well flat bottom microplates, to which 1 mg of compound is added per well (double in methanol) and evaporated to dryness. Compounds are redissolved in SGF and SIF and incubated overnight at 37 ° C. on a horizontal shaker. After filtration, the compound concentration is determined by UV-spectrophotometry.
Oral availability in rats and dogs Oral availability of selected series of compounds in a set of standard kinetic experiments, first in male and female rats, second in male and female Assess in dogs. The compound is prepared as a 20 mg / ml solution or suspension in DMSO, PEG400 or cyclodextrin 40% (CD40%) in water. For most experiments in rats, three dose groups were formed: 1 intraperitoneal dose at 20 mg / kg using 1 / DMSO formulation; 1 oral dose at 20 mg / kg using 2 / PEG400 formulation. Single oral dose at 20 mg / kg, using a standard dose and 3 / cyclodextrin formulation. For dogs, only the oral route of administration is used. Blood is sampled at regular time intervals after dosing and serum drug concentrations are determined using LC-MS bioanalytical methods.
Boosting systemic bioavailability
In the case of compounds of the type described (protease-inhibitors), inhibition of the metabolic degradation process reduces systemic clearance by reducing first-pass metabolism in the liver and metabolic clearance from plasma. It is known that availability can be significantly improved. This “boosting” principle can be applied to the pharmacological action of a drug in a clinical context. This principle can also be investigated in both rats or dogs by co-administration of compounds that inhibit Cyt-p45O metabolic enzymes. Known blocking agents are, for example, ritonavir and ketoconazole. Dosing ritonavir (RTV) at a single oral dose at 5 mg / kg in rats and dogs can significantly increase the systemic availability of the compounds of the invention added (reflected by improved AUC). ).
Protein binding analysis:
It is known that human serum proteins such as albumin (HSA) or alpha-1 acid glycoprotein (AAG) bind to many drugs, which can affect the effectiveness of these compounds. The anti-HIV activity of the compounds was measured in the presence of human serum, thus assessing the effect of protease inhibitor binding to those proteins.

MT4 cells are infected with HIV-1 LAI at a multiplicity of infection (MOI) of 0.001-0.01 CCID ₅₀ (50% cell culture infectious dose per cell, CCID ₅₀ ). After 1 hour incubation, the cells were washed and 10% FCS (fetal bovine serum), 10% FCS + 1 mg / ml AAG (α ₁ -acid glycoprotein), 10% FCS + 45 mg / ml HSA (human serum albumin) or 50% Plate in 96 well plates containing serial dilutions of compound in the presence of human serum (HS). After 5 or 6 days incubation, EC ₅₀ (50% effective concentration in cell-based assays) is calculated by determining cell viability or by quantifying the level of HIV replication. Cell viability is measured using the above assay. HIV (wild type or resistant strains) and MT4 cells in a 96 well plate containing serial dilutions of the compound in the presence of 10% FCS or 10% FCS + 1 mg / ml AAG, 200-250 CCID ₅₀ / well and 30 respectively. Add to a final concentration of 1,000 cells / well. After a 5-day incubation (37 ° C., 5% CO ₂ ), the tetrazolium colorimetric MTT (3- [4,5-dimethylthiazol-2-yl] -2,5-diphenyltetrazolium bromide) method (Pauwels et al. J. Virol. Methods 1998, 20, 309-321) to determine cell viability.
Preparation of Compound 3 Compound 3 was dissolved in an organic solvent such as ethanol, methanol or methylene chloride, preferably a mixture of ethanol and methylene chloride. Typically 5 mPa.s. Polymers of s, such as polyvinylpyrrolidone copolymer with vinyl acetate (PVP-VA) or hydroxypropylmethylcellulose (HPMC) were dissolved in an organic solvent such as ethanol, methanol, methylene chloride. Suitably the polymer was dissolved in ethanol. The polymer and compound solutions were mixed and subsequently spray dried. The compound / polymer ratio was chosen from 1/1 to 1/6. The middle range is 1 / 1.5 and 1/3. A suitable ratio was 1/6. The spray dried powder, solid dispersion was subsequently filled into capsules for administration. The drug placed in one capsule ranges from 50 to 100 mg depending on the size of the capsule used.
Film - active ingredient preparation 100g of coated tablets <br/> tablet cores, thoroughly mixed mixture of starch lactose and 200g of 570 g, the subsequent approximately 200ml of water 5g of sodium dodecyl sulfate and 10g polyvinylpyrrolidone solution Humidified with. The wet powder mixture was screened, dried and screened again. There was then added 100 g microcrystalline cellulose and 15 g hydrogenated vegetable oil. The whole was mixed well and compressed into tablets, giving 10.000 tablets each containing 10 mg of active ingredient.
Coating To a solution of 10 g methylcellulose in 75 ml denatured ethanol was added a solution of 5 g ethylcellulose in 150 ml dichloromethane. Then 75 ml of dichloromethane and 2.5 ml of 1,2,3-propanetriol were added thereto. 10 g of polyethylene glycol was melted and dissolved in 75 ml of dichloromethane. The latter solution was added to the former, and then 2.5 g magnesium octadecanoate, 5 g polyvinylpyrrolidone and 30 ml concentrated pigment suspension were added to homogenize the whole. The mixture thus obtained was coated on the tablet core in a coating apparatus.

Claims (32)

formula

[Where:
R ₁ and R ₈ are each independently hydrogen, C _1-6 alkyl, C _2-6 alkenyl, aryl C _1-6 alkyl, C _3-7 cycloalkyl, C _3-7 cycloalkyl C _1-6 alkyl, Aryl, Het ¹ , Het ¹ C _1-6 alkyl, Het ² , Het ² C _1-6 alkyl;
R ₁ is also a formula

Can also be a group of
Wherein R ₉ , R _10a and R _10b are each independently hydrogen, C _1-4 alkyloxycarbonyl, carboxyl, aminocarbonyl, mono- or di (C _1-4 alkyl) aminocarbonyl, C _3-7 cycloalkyl. , C _2-6 alkenyl, C _2-6 alkynyl, C _1-4 alkyl, or aryl, Het ¹ , Het ² , C _3-7 cycloalkyl, C _1-4 alkyloxycarbonyl, carboxyl, aminocarbonyl, mono- Or di (C _1-4 alkyl) aminocarbonyl, aminosulfonyl, C _1-4 alkyl S (O) _t , hydroxy, cyano, halogen, amino or mono- or disubstituted amino (where substitution on the amino group) groups are each independently C _1-4 alkyl, aryl, aryl C _1-4 alkyl, C _3-7 cycloalkyl, C _3-7 cycloalkyl C _1-4 alkyl, H ^{t 1, Het 2, Het 1} C 1-4 an alkyl and Het ² C _1-4 C _1-4 alkyl substituted with chosen) alkyl; wherein R _9, R _10a and they are attached to Carbon atoms can also form a C _3-7 cycloalkyl group; L is —O—C _1-6 alkanediyl-C (═O) — or —NR ₈ —C _1-6 alkanediyl-C In the case of (═O) —, R ₉ can also be oxo;
R _11a is hydrogen, C _2-6 alkenyl, C _2-6 alkynyl, C _3-7 cycloalkyl, aryl, aminocarbonyl, mono- or disubstituted aminocarbonyl, amino C _1-4 alkylcarbonyloxy, mono- Or di-substituted amino C _1-4 alkylcarbonyloxy, C _1-4 alkyloxycarbonyl, aryloxycarbonyl, Het ¹ oxycarbonyl, Het ² oxycarbonyl, aryloxycarbonyl C _1-4 alkyl, aryl C _1-4 Alkyloxycarbonyl, C _1-4 alkylcarbonyl, C _3-7 cycloalkylcarbonyl, C _3-7 cycloalkyl C _1-4 alkyloxycarbonyl, C _3-7 cycloalkylcarbonyloxy, carboxyl C _1-4 alkylcarbonyloxy , C _1-4 alkylcarbonyloxy, aryl C _1-4 alkyl carbonylation , Arylcarbonyloxy, aryloxycarbonyloxy, Het ¹ carbonyl, Het ¹ carbonyloxy, Het ¹ C _1-4 alkyloxycarbonyl, Het ² carbonyloxy, Het ² C _1-4 alkylcarbonyloxy, Het ² C _{1- 4} alkyloxycarbonyloxy, C _1-4 alkyl or aryl, aryloxy, be a C _1-4 alkyl substituted with Het ² or hydroxy; wherein the substituents on the amino groups are each independently C _{1- 4} alkyl, aryl, aryl C _1-4 alkyl, C _3-7 cycloalkyl, C _3-7 cycloalkyl C _1-4 alkyl, Het ¹ , Het ² , Het ¹ C _1-4 alkyl and Het ² C _1- Selected from ₄ alkyls;
R _11b is hydrogen, C _3-7 cycloalkyl, C _2-6 alkenyl, C _2-6 alkynyl, aryl, Het ¹ , Het ² , C _1-4 alkyl, or halogen, hydroxy, C _1-4 alkyl S ( ═O) _t , aryl, C _3-7 cycloalkyl, Het ¹ , Het ² , amino, mono- or disubstituted amino (wherein the substituents on the amino group are each independently C _1-4 alkyl, From aryl, aryl C _1-4 alkyl, C _3-7 cycloalkyl, C _3-7 cycloalkyl C _1-4 alkyl, Het ¹ , Het ² , Het ¹ C _1-4 alkyl and Het ² C _1-4 alkyl C _1-4 alkyl substituted with
Where R _11b can be attached to the rest of the molecule via a sulfonyl group;
each t is independently zero, 1 or 2;
R ₂ is hydrogen or C _1-6 alkyl;
L is —C (═O) —, —O—C (═O) —, —NR ₈ —C (═O) —, —O—C _1-6 alkanediyl-C (═O) —, —NR ₈ -C _1-6 alkanediyl-C (═O) —, —S (═O) ₂ —, —O—S (═O) ₂ —, —NR ₈ —S (═O) ₂ , where chosen here by C _1-6 alkanediyl moiety is human Dorokishi, aryl, Het ¹ and Het ^2; in C (= O) group or S (= O) or ₂ groups are bound to the NR ₂ moiety It may be substituted with a substituent;
R ₃ is C _1-6 alkyl, aryl, C _3-7 cycloalkyl, C _3-7 cycloalkyl C _1-4 alkyl or aryl C _1-4 alkyl;
R ₄ is hydrogen, C _1-4 alkyloxycarbonyl, carboxyl, aminocarbonyl, mono- or di (C _1-4 alkyl) aminocarbonyl, C _3-7 cycloalkyl, C _2-6 alkenyl, C _2-6 alkynyl. , C _1-6 alkyl or aryl, Het ¹ , Het ² , C _3-7 cycloalkyl, C _1-4 alkyloxycarbonyl, carboxyl, aminocarbonyl, mono- or di (C _1-4 alkyl) aminocarbonyl, Aminosulfonyl, C _1-4 alkyl S (═O) _t , hydroxy, cyano, halogen, amino and mono- or disubstituted amino (wherein the substituents on the amino group are each independently C _1-4 alkyl) , aryl, aryl C _1-4 alkyl, C _3-7 cycloalkyl, C _3-7 cycloalkyl -C _1-4 ^{alkyl, Het 1, Het 2, Het} 1 C 1-4 Al There the chosen) Le and Het ² C _1-4 alkyl each independently one or C _1-6 alkyl substituted more substituents which are selected;
R ₅ is hydrogen or C _1-6 alkyl;
R ₆ is hydrogen or C _1-6 alkyl; where the term “aryl” as a group or part of a group includes phenyl and naphthyl, both of which are unsubstituted or C _1-6 alkyl, amino C _1-6 alkyl, mono- or disubstituted amino C _1-6 alkyl, C _1-6 alkyloxy, halogen, hydroxy, hydroxy C _1-6 alkyl, amino, mono- or Disubstituted amino, nitro, cyano, halo C _1-6 alkyl, carboxyl, C _1-6 alkoxycarbonyl, C _3-7 cycloalkyl, Het ¹ , aminocarbonyl, mono- or disubstituted aminocarbonyl, methylthio Methylsulfonyl, phenyl, and C _1-6 alkyl, amino C _1-6 alkyl, mono- or disubstituted amino C _1-6 alkyl, C _1-6 alkyl Ruoxy, halogen, hydroxy, amino, mono- or disubstituted amino, nitro, cyano, halo C _1-6 alkyl, carboxyl, C _1-6 alkoxycarbonyl, C _3-7 cycloalkyl, Het ¹ , aminocarbonyl, Substituted with one or more substituents independently selected from phenyl substituted with one or more substituents independently selected from mono- or disubstituted aminocarbonyl, methylthio and methylsulfonyl Where the substituents that may be present on the amino function are C _1-6 alkyl, C _1-6 alkyloxy-A-, Het ¹ -A-, Het ¹ C _1-6 alkyl, Het ¹ C _1-6 alkyl -A-, Het ¹ oxy -A-, Het ¹ oxy C _1-4 alkyl -A-, phenyl -A-, phenyl - oxy - -, -A- phenyloxy C _1-4 alkyl, phenyl C _1-6 alkyl -A-, -A- C _1-6 alkyloxycarbonyl, amino -A-, amino C _1-6 alkyl and amino C _{1 -6} alkyl -A- are independently selected from wherein each of the amino groups with C _1-4 alkyl mono - or when possible di - may be substituted, is and wherein a C _{1- 6} alkanediyl, -C (= O) -, - C (= S) -, - S (= O) 2 -, C 1-6 alkanediyl -C (= O) -, C 1-6 alkanediyl - Defined as C (= S)-or C _1-6 alkanediyl-S (= O) _2- , where the point of attachment of A to the rest of the molecule contains a C _1-6 alkanediyl group In the moiety to be the group;
The term "Het ^1" as part of a single group or as a group, saturated or partially unsaturated monocyclic having a ring member of 3 to 14 ring members, a bicyclic or tricyclic heterocyclic Defined as a ring, which contains one or more heteroatom ring members each independently selected from nitrogen, oxygen or sulfur and which is unsubstituted or substituted on one or more carbon atoms _1-6 alkyl, amino C _1-6 alkyl, mono- or disubstituted amino C _1-6 alkyl,
Hydroxy C _1-6 alkyl, C _1-6 alkyloxy, halogen, hydroxy, oxo, amino, mono- or disubstituted amino, nitro, cyano, halo C _1-6 alkyl, carboxyl, C _1-6 alkoxycarbonyl , C _3-7 cycloalkyl, aminocarbonyl, mono- or disubstituted aminocarbonyl, methylthio, methylsulfonyl, aryl, and 3 to 14 ring members, each independently from nitrogen, oxygen or sulfur one or saturated or partially unsaturated monocyclic containing more than heteroatom ring members which are selected, can be substituted by a bicyclic or tricyclic heterocycle wherein on the amino functionality that may exist substituents C _1-6 alkyl, C _1-6 alkyloxy -A-, the aryl -A-, aryloxy -A-, Ally Oxy C _1-4 alkyl -A-, aryl C _1-6 alkyl -A-, -A- C _1-6 alkyloxycarbonyl, amino -A-, amino C _1-6 alkyl and amino C _1-6 alkyl are independently selected from -A-, wherein each amino group mono C _1-4 alkyl - if or possible di - may be substituted, and wherein a is as defined above Yes;
The term "Het ^2" as part of a single group or a group refers to an aromatic monocyclic having a ring member of 3 to 14 ring members, defined as the bicyclic or tricyclic heterocycle , It contains one or more heteroatom ring members each independently selected from nitrogen, oxygen or sulfur and is unsubstituted or C _1-6 alkyl on one or more carbon atoms Amino C _1-6 alkyl, mono- or disubstituted amino C _1-6 alkyl, hydroxy C _1-6 alkyl, C _1-6 alkyloxy, halogen, hydroxy, amino, mono- or disubstituted amino , nitro, cyano, halo C _1-6 alkyl, carboxyl, C _1-6 alkoxycarbonyl, C _3-7 cycloalkyl, aminocarbonyl, mono- - or di-substituted Aminokaru Sulfonyl, methylthio, methylsulfonyl, aromatic monocyclic having from 3 to 12 ring members in aryl Le rabbi, can be substituted by a bicyclic or tricyclic heterocyclic ring; wherein amino functionality substituents C _1-6 alkyl which may be present on, C _1-6 alkyloxy -A-, the aryl -A-, aryloxy -A-, -A- aryloxy C _1-4 alkyl, aryl C _{1 -6} alkyl-A-, C _1-6 alkyloxycarbonylamino-A-, amino-A-, amino C _1-6 alkyl and amino C _1-6 alkyl-A-, wherein amino each group mono C _1-4 alkyl - if or possible di - may be substituted, is and wherein a is as defined above]
, Their salts, stereoisomers or racemic mixtures. R ₉ , R _10a and R _10b are each independently hydrogen, C _1-4 alkyloxycarbonyl, carboxyl, aminocarbonyl, mono- or di (C _1-4 alkyl) aminocarbonyl, C _3-7 cycloalkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _1-4 alkyl, or aryl, Het ¹ , Het ² , C _3-7 cycloalkyl, C _1-4 alkyloxycarbonyl, carboxyl, aminocarbonyl, mono- or di (C _1-4 alkyl) aminocarbonyl, aminosulfonyl, C _1-4 alkyl S (O) _t , hydroxy, cyano, halogen, amino or mono- or disubstituted amino (wherein the substituents on the amino group are C _1-4 alkyl, aryl, aryl C _1-4 alkyl, C _3-7 cycloalkyl, C _3-7 cycloalkyl C _1-4 alkyl, Het ^1, Het ^2, the He ¹ C _1-4 alkyl and Het ² C _1-4 selected from alkyl) be a C _1-4 alkyl substituted with; wherein R _9, R _10a and the carbon atom to which they are attached also C ₃ Can also form a _-7 cycloalkyl group;
R _11b is hydrogen, C _3-7 cycloalkyl, C _2-6 alkenyl, C _2-6 alkynyl, aryl, Het ¹ , Het ² , C _1-4 alkyl, or halogen, hydroxy, C _1-4 alkyl S ( ═O) _t , aryl, C _3-7 cycloalkyl, Het ¹ , Het ² , amino, mono- or disubstituted amino (wherein the substituents on the amino group are C _1-4 alkyl, aryl, aryl C _1-4 alkyl, C _3-7 cycloalkyl, C _3-7 cycloalkyl C _1-4 alkyl, selected from Het ¹ , Het ² , Het ¹ C _1-4 alkyl and Het ² C _1-4 alkyl) Substituted C _1-4 alkyl;
Where R _11b can be attached to the rest of the molecule via a sulfonyl group;
t is zero, 1 or 2;
L is —C (═O) —, —O—C (═O) —, —NR ₈ —C (═O) —, —O—C _1-6 alkanediyl-C (═O) —, —NR ₈ -C _1-6 alkanediyl-C (═O) —, —S (═O) ₂ —, —O—S (═O) ₂ —, —NR ₈ —S (═O) ₂ , where And either the C (═O) group or the S (═O) ₂ group is bound to the NR ₂ moiety;
R ₄ is hydrogen, C _1-4 alkyloxycarbonyl, carboxyl, aminocarbonyl, mono- or di (C _1-4 alkyl) aminocarbonyl, C _3-7 cycloalkyl, C _2-6 alkenyl, C _2-6 alkynyl , C _1-6 alkyl or aryl, Het ¹ , Het ² , C _3-7 cycloalkyl, C _1-4 alkyloxycarbonyl, carboxyl, aminocarbonyl, mono- or di (C _1-4 alkyl) aminocarbonyl, Aminosulfonyl, C _1-4 alkyl S (═O) _t , hydroxy, cyano, halogen, amino and mono- or disubstituted amino (wherein the substituents on the amino group are C _1-4 alkyl, aryl, aryl C _1-4 alkyl, C _3-7 cycloalkyl, C _3-7 cycloalkyl C _1-4 alkyl, Het ¹ , Het ² , Het ¹ C _1-4 alkyl and Het ² C One or A compound according to claim 1 in more substituents is C _1-6 alkyl substituted selected from chosen) from _1-4 alkyl. R ₁ is hydrogen, C _1-6 alkyl, C _2-6 alkenyl, aryl C _1-6 alkyl, C _3-7 cycloalkyl, C _3-7 cycloalkyl C _1-6 alkyl, aryl, Het ² or Het ² The compound according to claim 1, which is C _1-6 alkyl. The compound according to any one of claims 1 to 3, wherein R ₁ -L is Het ¹ -OC (= O)-. R ₁ -L is Het ² -C _1-6 alkanediyl-O—C (═O) —, aryl-O—C _1-6 alkanediyl-C (═O) — or aryl-C (═O) —. The compound according to any one of claims 1 to 3. R ₁ is Het ² or Het ² C _1-6 alkyl; wherein Het ² contains at least one heteroatom independently selected from nitrogen, oxygen and sulfur;
L is -C (= O) -, - O-C (= O) - or O-C _1-6 alkyl -C (= O) - A compound according to claim 1 which is . R ₁ is Het ² or Het ² C _1-6 alkyl; wherein Het ² contains at least two heteroatoms each independently selected from nitrogen, oxygen and sulfur;
L is -C (= O) -, - O-C (= O) - or O-C _1-6 alkyl -C (= O) - A compound according to claim 1 which is . R ₁ is 2-thiazolylmethyl-;
L is -OC (= O)-, The compound of any one of Claims 1-3. R ₁ is Het ¹ or Het ¹ C _1-6 alkyl, wherein Het ¹ contains at least one heteroatom independently selected from nitrogen, oxygen and sulfur;
L is -C (= O) -, - O-C (= O) - or O-C _1-6 alkyl -C (= O) - A compound according to claim 1 which is . Construction

Or a salt thereof . 11. A compound according to any one of claims 1 to 10 in the form of a pharmaceutically acceptable salt. A pharmaceutical composition comprising an effective amount of at least one compound according to any one of claims 1 to 11 and a pharmaceutically acceptable excipient. An inhibitor of a retroviral protease in a mammal infected with a retrovirus, comprising the compound according to any one of claims 1 to 11 as an active ingredient. An agent for treating or controlling an infection or disease associated with a retroviral infection in a mammal, comprising at least one compound according to any one of claims 1 to 11 as an active ingredient. A mammal is combined with at least one first compound according to any one of claims 1 to 11 and at least one second compound that regulates metabolism of the first compound, Wherein the second compound can be administered simultaneously, separately or sequentially with the first compound, for treating or controlling an infection or disease associated with a retroviral infection in a mammal.   The drug according to any one of claims 13 to 15, wherein the mammal is a human. An inhibitor of retrovirus replication comprising at least one compound according to any one of claims 1 to 11 as an active ingredient.   The agent according to claim 17, wherein the retrovirus is human immunodeficiency virus (HIV).   The drug according to claim 18, wherein the HIV virus is a multidrug resistant strain. Use of a compound according to any one of claims 1 to 11 in the manufacture of a medicament for the treatment or control of an infection or disease associated with a retroviral infection in a mammal. Use of a compound according to any one of claims 1 to 11 in the manufacture of a medicament for inhibiting a retroviral protease in a mammal infected with a retrovirus. Use of a compound according to any one of claims 1 to 11 in the manufacture of a medicament for the inhibition of retrovirus replication.   23. Use of a compound according to any one of claims 20 to 22 wherein the retrovirus is human immunodeficiency virus (HIV).   The use of a compound according to any one of claims 20 to 23, wherein the retrovirus is a multidrug resistant strain. The following compounds:

The compound of Claim 1 or 2 selected from these. A pharmaceutical composition comprising a solid dispersion comprising (a) a compound according to any one of claims 1 to 11 , (b) one or more pharmaceutically acceptable water-soluble polymers. Construction

Or a salt, stereoisomer or racemic mixture thereof. Construction

28. The compound according to claim 27, a salt thereof, a stereoisomer or a racemic mixture. Construction

28. The compound according to claim 27, a salt thereof, a stereoisomer or a racemic mixture.   30. A compound having the structure of any one of claims 27 to 29, wherein the compound is in its free base form.   A salt of the compound having the structure according to any one of claims 27 to 29.   A hydrate or solvate of the compound having the structure according to any one of claims 27 to 29.